Process and intermediates for the production of ccr2 antagonists

ABSTRACT

The present invention relates to a process for the production of novel antagonists for CCR2 (CC chemokine receptor 2) and intermediates thereof.

FIELD OF INVENTION

The present invention relates to novel antagonists for CCR2 (CC chemokine receptor 2) and their use for providing medicaments for treating conditions and diseases where activation of CCR2 plays a causative role, especially pulmonary diseases like asthma and COPD, neurologic disease, especially of pain diseases, immune related diseases, especially diabetes mellitus including diabetes nephropathy, and cardiovascular diseases, especially atherosclerotic disease.

BACKGROUND OF THE INVENTION

The chemokines are a family of small, proinflammatory cytokines, with potent chemotactic activities. Chemokines are chemotactic cytokines that are released by a wide variety of cells to attract various cells, such as monocytes, macrophages, T cells, eosinophils, basophils and neutrophils to sites of inflammation.

Chemokine receptors, such as CCR2 or CCR5 have been implicated as being important mediators of inflammatory and immunoregulatory disorders and diseases as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. Accordingly, agents which modulate chemokine receptors such as the CCR2 and CCR5 receptor would be useful in such disorders and diseases.

In particular it is widely accepted that numerous conditions and diseases involve inflammatory processes. Such inflammations are critically triggered and/or promoted by the activity of macrophages, which are formed by differentiation out of monocytes. It has further been found that monocytes are characterized by, e.g., a high expression of membrane-resident CCR2, whereas the CCR2 expression in macrophages is lower. CCR2 is a critical regulator of monocytes trafficking, which can be described as the movement of the monocytes towards an inflammation along a gradient of monocyte chemoattractant proteins (MCP-1, MCP-2, MCP-3, MCP-4).

Therefore, in order to reduce macrophage-induced inflammation, it would be desirable to block the monocyte CCR2 by an antagonist, so that the monocytes can be less triggered to move towards an inflammation area for conversion into macrophages.

Based on the aforesaid there is a need for providing effective antagonists for CCR2, which are pharmacologically acceptable.

DESCRIPTION OF THE INVENTION

It has now been found that such effective CCR2 inhibitors can be provided by compounds according to general formula (I),

wherein R₁ is -L₁-R₇,

wherein L₁ is a linker selected from a bond or a group selected from —C₁-C₂-alkylene, and —C₁-C₂-alkenylene which optionally comprises one or more groups selected from —O—, —C(O)—, and —NH— in the chain and which is optionally substituted by a group selected from among —OH, —NH₂, —C₁-C₃-alkyl, O—C₁-C₆-alkyl, and —CN,

wherein R₇ is a ring selected from among —C₃-C₈-cycloalkyl, —C₃-C₈-heterocyclyl, —C₅-C₁₀-aryl, and —C₅-C₁₀-heteroaryl,

wherein the ring R₇ is optionally substituted with one or more groups selected from among —CF₃, —O—CF₃, —CN, and -halogen,

or wherein the ring R₇ is optionally substituted with one or more groups selected from among —C₁-C₆-alkyl, —O—C₁-C₆-alkyl, —C₅-C₁₀-aryl, —C₅-C₁₀-heteroaryl, —C₃-C₈-cycloalkyl, —C₃-C₈-heterocyclyl, —C₁-C₆-alkenyl, and —C₁-C₆-alkynyl, optionally being further substituted by one or more groups selected from —OH, —NH₂, —C₁-C₃-alkyl, —O—C₁-C₆-alkyl, —CN, —CF₃, —OCF₃, halogen, and ═O,

or wherein the ring R₇ is optionally further bi-valently substituted on two neighbouring ring atoms, such that an annellated ring is formed by one or more groups selected from among —C₁-C₆-alkylene, —C₂-C₆-alkenylene and —C₄-C₆-alkynylene, in which one or two carbon centers may optionally by replaced by 1 or 2 hetero atoms selected from N, O and S, the bivalent group being optionally substituted by one or more groups selected from —OH, —NH₂, —C₁-C₃-alkyl, —O—C₁-C₆-alkyl, —CN, —CF₃, —OCF₃, halogen, and ═O;

R₂ is selected from among —H, -halogen, —CN, —O—C₁-C₄-alkyl, —C₁-C₄-alkyl, —CH═CH₂, —C≡CH, —CF₃, —OCF₃, —OCF₂H, and —OCFH₂;

R₃ is selected from among —H, -methyl, -ethyl, -propyl, -i-propyl, -cyclopropyl, —OCH₃, and —CN;

R₄ and R₅ are independently selected from among an electron pair, —H, —C₁-C₆-alkyl, —NH₂, —C₃-C₈-cycloalkyl, —C₃-C₈-heterocyclyl, —C₅-C₁₀-aryl, —C₅-C₁₀-heteroaryl, and —C(O)—N(R₈,R_(8′)),

with R₈ and R_(8′) independently being selected from among —H and —C₁-C₆-alkyl, wherein R₄ and R₅ if different from an electron pair or —H are optionally independently substituted with one or more groups selected from among -halogen, —OH, —CF₃, —CN, —C₁-C₆-alkyl, —O—C₁-C₆-alkyl, —O—C₃-C₈-cycloalkyl, —O—C₃-C₈-heterocyclyl, —O—C₅-C₁₀-aryl, —O—C₅-C₁₀-heteroaryl, —C₀-C₆-alkylene-CN, —C₀-C₄-alkylene-O—C₁-C₄-alkyl, —C₀-C₄-alkylene-O—C₃-C₈-cycloalkyl, —C₀-C₄-alkylene-O—C₃-C₈-heterocyclyl, —C₀-C₄-alkylene-O—C₅-C₁₀-aryl, —C₀-C₄-alkylene-O—C₅-C₁₀-heteroaryl, —C₀-C₄-alkylene-Q-C₀-C₄-alkyl-N(R₉,R_(9′)), —C₀-C₄-alkylene-N(R₁₀)-Q-C₁-C₄-alkyl, —C₀-C₄-alkylene-N(R₁₀)-Q-C₃-C₈-cycloalkyl, —C₀-C₄-alkylene-N(R₁₀)-Q-C₃-C₈-heterocyclyl, —C₀-C₄-alkylene-N(R₁₀)-Q-C₅-C₁₀-aryl, —C₀-C₄-alkylene-N(R₁₀)-Q-C₅-C₁₀-heteroaryl, —C₀-C₄-alkylene-Q-N(R₁₁,R_(11′)), —C₀-C₄-alkylen-N(R₁₂)-Q-N(R₁₃,R_(13′)), —C₀-C₄-alkylen-R₁₄, —C₀-C₄-alkylene-Q-C₁-C₆-alkyl, —C₀-C₄-alkylene-Q-C₃-C₈-cycloalkyl, —C₀-C₄-alkylene-Q-C₃-C₈-heterocyclyl, —C₀-C₄-alkylene-Q-C₅-C₁₀-aryl, —C₀-C₄-alkylene-Q-C₅-C₁₀-heteroaryl, —C₀-C₄-alkylene-O-Q-N(R₁₅,R_(15′)), and —C₀-C₄-alkylene-N(R₁₆)-Q-O—(R₁₇)

wherein Q is selected from among —C(O)— and —SO₂—

wherein R₁₂, R₁₆, are independently selected from among —H, —C₁-C₆-alkyl, and —C₃-C₆-cycloalkyl,

wherein R₉, R_(9′), R₁₀, R₁₁, R_(11′), R₁₃, R_(13′), R₁₅, R_(15′) are independently selected from among —H and —C₁-C₆-alkyl, and —C₃-C₆-cycloalkyl,

or wherein R₉ and R_(9′), R₁₁ and R_(11′), R₁₃ and R_(13′), R₁₅ and R_(15′), together form a —C₂-C₆-alkylene group, preferably a —C₅-C₆-alkylene group,

wherein R₁₄ and R₁₇ are independently selected from among —H, —C₁-C₆-alkyl, —C₅-C₁₀-aryl, —C₅-C₁₀-heteroaryl, —C₃-C₈-cycloalkyl, and —C₃-C₈-heterocyclyl, wherein said —C₃-C₈-heterocyclyl optionally comprises nitrogen and/or —SO₂— in the ring, and wherein R₁₄ and R₁₇ are optionally substituted with one or more groups selected from among —OH, —OCH₃, —CF₃, —OCF₃, —CN, -halogen, —C₁-C₄-alkyl, ═O, and —SO₂—C₁-C₄-alkyl,

or wherein R₄ and/or R₅ are independently a group of the structure -L₂-R₁₈,

wherein L₂ is selected from among —NH—, and —N(C₁-C₄-alkyl)-,

wherein R₁₈ is selected from among —C₅-C₁₀-aryl, —C₅-C₁₀-heteroaryl, —C₃-C₈-cycloalkyl, and —C₃-C₈-heterocyclyl,

wherein R₁₈ is optionally substituted by one or more groups selected from among halogen, —CF₃, —OCF₃, —CN, —OH, —O—C₁-C₄-alkyl, —C₁-C₆-alkyl, —NH—C(O)—C₁-C₆-alkyl, —N(C₁-C₄-alkyl)-C(O)—C₁-C₆-alkyl, —C(O)—C₁-C₆-alkyl, —S(O)₂—C₁-C₆-alkyl, —NH—S(O)₂—C₁-C₆-alkyl, —N(C₁-C₄-alkyl)-S(O)₂—C₁-C₆-alkyl, and —C(O)—O—C₁-C₆-alkyl,

and wherein R₄, R₅ and R₁₈ are optionally further substituted by spiro-C₃-C₈-cycloalkyl or spiro-C₃-C₈-heterocyclyl such that together with R₄, R₅ and/or R₁₈ a spirocycle is formed, wherein said spiro-C₃-C₈-heterocyclyl optionally comprises one or more groups selected from among nitrogen, —C(O)—, —SO₂—, and —N(SO₂—C₁-C₄-alkyl)- in the ring,

or wherein R₄, R₅ and R₁₈ are optionally further bi-valently substituted by one or more spirocyclic or annellated ring forming groups selected from among —C₁-C₆-alkylene, —C₂-C₆-alkenylene, and —C₄-C₆-alkynylene, in which one ore two carbon centers may optionally be replaced by one or two hetero atoms selected from among N, O and S and which may optionally be substituted by one or more groups on one ring atom or on two neighbouring ring atoms selected from among —OH, —NH₂, —C₁-C₃-alkyl, 0-C₁-C₆-alkyl, —CN, —CF₃, —OCF₃, and halogen;

R₆ is selected from among —H, —C₁-C₄-alkyl, —OH, —O—C₁-C₄-alkyl, -halogen, —CN, —CF₃, and —OCF₃;

A is selected from among a single bond, ═CH—, —CH₂—, —O—, —S—, and —NH—;

n is 1, 2 or 3;

Z is C or N,

as well as in form of their acid addition salts with pharmacologically acceptable acids, as well as in form of their solvates and/or hydrates.

Preferred compounds of formula (I) according to the invention are compounds with R₂, R₃, R₄, R₅, R₆, R₈, R_(8′), R₉, R_(9′), R₁₀, R₁₁, R_(11′)R₁₂, R₁₃, R_(13′), R₁₄, R₁₅, R_(15′), R₁₆, R₁₇, R₁₈, A, L₂, Z, Q, and n as herein before or below defined, wherein R₁ is -L₁-R₇,

with L₁ being a linker selected from a bond or a group selected from among —C₁-C₂-alkylene, and —C₁-C₂-alkenylene optionally comprising one or more groups selected from among —O—, —C(O)—, and, —NH— in the chain and optionally being substituted by a group selected from among —OH, —NH₂, —C₁-C₃-alkyl, 0-C₁-C₆-alkyl, and —CN,

wherein R₇ is a ring selected from among —C₃-C₈-cycloalkyl, —C₅-C₁₀-aryl, —C₃-C₈-heterocyclyl comprising 1 or 2 hetero atoms selected from among N, and O, and —C₅-C₁₀-heteroaryl comprising 1 or 2 hetero atoms selected from among N, and O,

wherein the ring R₇ is optionally substituted with one or more groups selected from among —CF₃, —O—CF₃, —CN, and -halogen,

or wherein the ring R₇ is optionally substituted with one or more groups selected from among —C₁-C₆-alkyl, —O—C₁-C₆-alkyl, —C₅-C₁₀-aryl, —C₃-C₈-cycloalkyl, —C₃-C₈-heterocyclyl, —C₁-C₆-alkenyl, and —C₁-C₆-alkynyl, optionally being substituted by one or more groups selected from —OH, —NH₂, —C₁-C₃-alkyl, —O—C₁-C₆-alkyl, —CN, —CF₃, —OCF₃, halogen, and ═O,

or wherein the ring R₇ is optionally further bi-valently substituted by one or more annellated ring forming groups selected from among —C₁-C₆-alkylene, —C₂-C₆-alkenylene and —C₄-C₆-alkynylene, in which one or two carbon centers may optionally by replaced by 1 or 2 hetero atoms selected from N, and O, wherein the bivalent group is optionally substituted by one or more groups selected from —OH, —NH₂, —C₁-C₃-alkyl, —O—C₁-C₆-alkyl, —CN, —CF₃, —OCF₃, halogen, and ═O;

Preferred compounds of formula (I) according to the invention are compounds with R₂, R₃, R₄, R₅, R₆, R₈, R_(8′), R₉, R_(9′), R₁₀, R₁₁, R_(11′)R₁₂, R₁₃, R_(13′), R₁₄, R₁₅, R_(15′), R₁₆, R₁₇, R₁₈, A, L₂, Z, Q, and n as herein before or below defined, wherein R₁ is -L₁-R₇,

wherein L₁ is a linker selected from among a bond, methylene, ethylene, methenylene, and ethenylene,

wherein L₁, if different from a bond, is optionally substituted with one or more groups selected from among methyl, and ethyl,

wherein R₇ is a ring selected from among cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, pyrrolidinyl, piperidinyl, azepanyl, tetrahydrofuranyl, tetrahydropyranyl, oxepanyl, phenyl, pyridyl, and furanyl,

wherein the ring R₇ is optionally substituted with one or more groups selected from among —F, —Cl, -methyl, -ethyl, -propyl, -i-propyl, -cyclopropyl, -t-butyl, —CF₃, —O—CF₃, —CN, —O-methyl, -furanyl and -phenyl, wherein said furanyl and said phenyl are optionally independently substituted by one or more groups selected from among —C₁-C₆-alkyl, or halogen, —OCH₃, —CF₃, and —OCF₃.

or wherein R₇ is bi-valently substituted by one or more groups selected from among

on two neighbouring ring atoms, such that an annellated ring is formed.

Preferred compounds of formula (I) according to the invention are compounds with R₂, R₃, R₄, R₅, R₆, R₇, R₈, R_(8′), R₉, R_(9′), R₁₀, R₁₁, R_(11′) R₁₂, R₁₃, R_(13′), R₁₄, R₁₅, R_(15′) R₁₆, R₁₇, R₁₈, A, L₂, Z, Q, and n as herein before or below defined, wherein R₁ is -L₁-R₇,

and wherein L₁ is a linker selected from among a bond, methylene, ethylene, methenylene, and ethenylene and wherein L₁ is optionally substituted with one or more of methyl or ethyl and wherein L₁ optionally comprises one or more —O— atoms.

Preferred compounds of formula (I) according to the invention are compounds with R₂, R₃, R₄, R₅, R₆, R₇, R₈, R_(8′), R₉, R_(9′), R₁₀, R₁₁, R_(11′) R₁₂, R₁₃, R_(13′), R₁₄, R₁₅, R_(15′) R₁₆, R₁₇, R₁₈, A, L₂, Z, Q, and n as herein before or below defined, wherein R₁ is selected from among

Preferred compounds of formula (I) according to the invention are compounds with R₁, R₃, R₄, R₅, R₆, R₇, R₈, R_(8′), R₉, R_(9′), R₁₀, R₁₁, R_(11′), R₁₂, R₁₃, R_(13′), R₁₄, R₁₅, R_(15′), R₁₆, R₁₇, R₁₈, A, L₁, L₂, Z, Q, and n as herein before or below defined, wherein R₂ is selected from among —H, -methyl, -ethyl, -propyl, -i-propyl, -cyclopropyl, -butyl, -i-butyl, -t-butyl, —F, —Cl, —Br, —I, —CN, —CH═CH₂, —C≡CH, and —OCH₃, more preferred from among H, -methyl, -ethyl, -propyl, -i-propyl, -cyclopropyl, and —OCH₃.

Preferred compounds of formula (I) according to the invention are compounds with R₁, R₃, R₄, R₅, R₆, R₇, R₈, R_(8′), R₉, R_(9′), R₁₀, R₁₁, R_(11′), R₁₂, R₁₃, R_(13′), R₁₄, R₁₅, R_(15′), R₁₆, R₁₇, R₁₈, A, L₁, L₂, Z, Q, and n as herein before or below defined, wherein R₂ is selected from among —H, -Methyl, -Ethyl, —Br, and —OCH₃.

Preferred compounds of formula (I) according to the invention are compounds with R₁, R₂, R₄, R₅, R₆, R₇, R₈, R_(8′), R₉, R_(9′), R₁₀, R₁₁, R_(11′), R₁₂, R₁₃, R_(13′), R₁₄, R₁₅, R_(15′), R₁₆, R₁₇, R₁₈, A, L₁, L₂, Z, Q, and n as herein before or below defined, wherein R₃ is selected from among —H, and -methyl.

Preferred compounds of formula (I) according to the invention are compounds with R₁, R₂, R₃, R₆, R₇, R₉, R_(9′), R₁₀, R₁₁, R_(11′), R₁₂, R₁₃, R_(13′), R₁₄, R₁₅, R_(15′), R₁₆, R₁₇, R₁₈, A, L₁, L₂, Z, Q, and n as herein before or below defined, wherein R₄ and R₅ are independently selected from among an electron pair, —H, -i-propyl, -amino, -pyrrolidinyl, -piperidinyl, -morpholinyl, -azepanyl, -oxazepanyl, -piperazinyl, -azetidinyl, -tetrahydropyranyl, -cyclopentyl, -cyclohexyl, and —C(O)—N(R₈,R_(8′)), with R₈ and R_(8′) independently being selected from among —H and —C₁-C₆-alkyl,

wherein R₄ and R₅ are optionally independently substituted with one or more groups selected from among -fluoro, -methyl, -ethyl, propyl, -i-propyl, -butyl, -i-butyl, -t-butyl, -hydroxy, —CF₃, —OCF₃, —CN, —O—CH₃, —O—C₂H₅, —O—C₃H₇, —CH₂—CN, —CH₂—O—CH₃, —(CH₂)₂—O—CH₃, —C(O)—CH₃, —C(O)—C₂H₅, —C(O)—C₃H₇, —COOH, —C(O)—NH₂, —C(O)—NH—CH₃, —C(O)—N(CH₃)₂, —NH—C(O)—CH₃, —N(CH₃)C(O)—CH₃, —NH—C(O)—C₂H₅, —N(CH₃)—C(O)—C₂H₅, —NH—C(O)—C₃H₇, —N(CH₃)—C(O)—C₃H₇, —NH—SO₂—CH₃, —N(CH₃)—SO₂—CH₃, —N(C₂H₅)—SO₂—CH₃, —N(C₃H₇)—SO₂—CH₃, —NH—SO₂—C₂H₅, —N(CH₃)—SO₂—C₂H₅, —N(C₂H₅)—SO₂—C₂H₅, —N(C₃H₇)—SO₂—C₂H₅, —NH—SO₂—C₃H₇, —N(CH₃)—SO₂—C₃H₇, —N(C₂H₅)—SO₂—C₃H₇, —N(C₃H₇)—SO₂—C₃H₇, —NH—SO₂—C₃H₅, —N(CH₃)—SO₂—C₃H₅, —N(C₂H₅)—SO₂—C₃H₅, —N(C₃H₇)—SO₂—C₂H₅, —CH₂—NH—SO₂—CH₃, —CH₂—N(CH₃)—SO₂—CH₃, —CH₂—NH—SO₂—C₂H₅, —CH₂—N(CH₃)—SO₂—C₂H₅, —CH₂—NH—SO₂—C₃H₇, —CH₂—N(CH₃)—SO₂—C₃H₇, —CH₂—NH—SO₂—C₃H₅, —CH₂—N(CH₃)—SO₂—C₃H₅, —NH—C(O)—NH₂, —N(CH₃)—C(O)—NH₂, —NH—C(O)—NH—CH₃, —N(CH₃)—C(O)—NH—CH₃, —NH—C(O)—N(CH₃)₂, —N(CH₃)—C(O)—N(CH₃)₂, —SO₂—NH₂, —SO₂—NH(CH₃), —SO₂—N(CH₃)₂, —C(O)—NH—C₂H₅, —C(O)—N(CH₃)—C₂H₅, —C(O)—N(CH₃)—C₃H₇, —C(O)—N(CH₃)—C₄H₉, —C(O)—NH—CH(CH₃)—C₂H₅, —C(O)—N(CH₃)—CH(CH₃)—C₂H₅, —CH₂—C(O)—NH₂, —CH₂—C(O)—NH—CH₃, —CH₂—C(O)—N(CH₃)₂, —N(CH₃)—SO₂—N(CH₃)₂, -phenyl, -pyridin-4-yl, —CH₂-3-methyl-oxetan-3-yl, —O-1,2-difluoro-phen-5-yl, —O-pyridin-2-yl, -pyrrolidine-2-one-1-yl, -3,5-dimethyl-[1,2,4]triazol-4-yl, -3-methyl-[1,2,4]oxadiazol-5-yl,

Preferred compounds of formula (I) according to the invention are compounds with R₁, R₂, R₃, R₆, R₇, R₈, R_(8′), R₉, R_(9′), R₁₀, R₁₁, R_(11′), R₁₂, R₁₃, R_(13′), R₁₄, R₁₅, R_(15′), R₁₆, R₁₇, R₁₈, A, L₁, L₂, Z, Q, and n as herein before or below defined, wherein R₄ and R₅ are independently selected from among an electron pair, —H, -amino, -piperidinyl, -tetrahydropyranyl, and -pyrrolidinyl, wherein R₄ and R₅ are optionally independently substituted with one or more groups selected from among -fluoro, —CF₃, -hydroxy, —O—CH₃, —OCF₃, —CN, —NH—SO₂—CH₃, —N(CH₃)—SO₂—CH₃, —N(C₂H₅)—SO₂—CH₃, —N(C₃H₇)—SO₂—CH₃, —NH—SO₂—C₂H₅, —N(CH₃)—SO₂—C₂H₅, —N(C₂H₅)—SO₂—C₂H₅, —N(C₃H₇)—SO₂—C₂H₅, —NH—SO₂—C₃H₇, —N(CH₃)—SO₂—C₃H₇, —N(C₂H₅)—SO₂—C₃H₇, —N(C₃H₇)—SO₂—C₃H₇, —NH—SO₂—C₃H₅, —N(CH₃)—SO₂—C₃H₅, —N(C₂H₅)—SO₂—C₃H₅, —N(C₃H₇)—SO₂—C₂H₅, —CH₂—NH—SO₂—CH₃, —CH₂—N(CH₃)—SO₂—CH₃, —CH₂—NH—SO₂—C₂H₅, —CH₂—N(CH₃)—SO₂—C₂H₅, —CH₂—NH—SO₂—C₃H₇, —CH₂—N(CH₃)—SO₂—C₃H₇, —CH₂—NH—SO₂—C₃H₅, —CH₂—N(CH₃)—SO₂—C₃H₅, —NH—C(O)—NH₂, —N(CH₃)—C(O)—NH₂, —NH—C(O)—NH—CH₃, —N(CH₃)—C(O)—NH—CH₃, —NH—C(O)—N(CH₃)₂, —N(CH₃)—C(O)—N(CH₃)₂, —SO₂—NH₂, —SO₂—NH(CH₃), —SO₂—N(CH₃)₂, —C(O)—NH—C₂H₅, —C(O)—N(CH₃)—C₂H₅, —C(O)—N(CH₃)—C₃H₇, —C(O)—N(CH₃)—C₄H₉, —C(O)—NH—CH(CH₃)—C₂H₅, —C(O)—N(CH₃)—CH(CH₃)—C₂H₅, —CH₂—C(O)—NH₂, —CH₂—C(O)—NH—CH₃, —CH₂—C(O)—N(CH₃)₂, —N(CH₃)—SO₂—N(CH₃)₂, -pyridin-4-yl, —CH₂-3-methyl-oxetan-3-yl, —O-1,2-difluoro-phen-5-yl, —O-pyridin-2-yl, -pyrrolidine-2-one-1-yl, -3,5-dimethyl-[1,2,4]triazol-4-yl, -3-methyl-[1,2,4]oxadiazol-5-yl,

Preferred compounds of formula (I) according to the invention are compounds with R₁, R₂, R₃, R₆, R₇, R₈, R_(8′), R₉, R_(9′), R₁₀, R₁₁, R_(11′), R₁₂, R₁₃, R_(13′), R₁₄, R₁₅, R_(15′), R₁₆, R₁₇, A, L₁, Z, Q, and n as herein before or below defined, wherein R₄ and R₅ are independently a group of the structure -L₂-R₁₈, wherein L₂ is selected from among —NH—, —N(CH₃)— and —N(C₂H₅)—, wherein R₁₈ is selected from among -tetrahydropyranyl, -cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl, -cycloheptyl, -cyclooctyl, -pyrrolidinyl, -piperidinyl, -piperazinyl, -morpholinyl, -chromanyl, -octahydro-pyrano-pyrrolyl, -octahydro-pyrano-pyridinyl, -octahydro-pyrano-oxazinyl, -oxaspirodecanyl, and -tetrahydro-naphthyridinyl, wherein R₁₈ is optionally substituted by one or more groups selected from among —F, —CF₃, —OCF₃, —CN, —OH, —O—CH₃, —CH₃, —NH—C(O)—CH₃, —N(CH₃)—C(O)—CH₃, —C(O)—CH₃, —S(O)₂—CH₃, —NH—S(O)₂—CH₃, —N(CH₃)—S(O)₂—CH₃, and —C(O)—O—C₂H₅.

Preferred compounds of formula (I) according to the invention are compounds with R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R_(8′), R₉, R_(9′), R₁₀, R₁₁, R_(11′), R₁₂, R₁₃, R_(13′), R₁₄, R₁₅, R_(15′), R₁₆, R₁₇, R₁₈, A, L₁, L₂, Z, Q, and n as herein before or below defined, wherein R₄, R₅ and R₁₈ are optionally further bi-valently substituted by one or more groups selected from among

on one ring atom or on two neighboring ring atoms, such that spirocyclic or annellated rings are formed.

Preferred compounds of formula (I) according to the invention are compounds with R₁, R₂, R₃, R₅, R₆, R₇, R₈, R_(8′), R₉, R_(9′), R₁₀, R₁₁, R_(11′), R₁₂, R₁₃, R_(13′), R₁₄, R₁₅, R_(15′), R₁₆, R₁₇, R₁₈, A, L₁, L₂, Z, Q, and n as herein before or below defined, wherein R₄ is selected from among

Preferred compounds of formula (I) according to the invention are compounds with R₁, R₂, R₃, R₄, R₆, R₇, R₈, R_(8′), R₉, R_(9′), R₁₀, R₁₁, R_(11′), R₁₂, R₁₃, R_(13′), R₁₄, R₁₅, R_(15′), R₁₆, R₁₇, R₁₈, A, L₁, L₂, Z, Q, and n as herein before or below defined, wherein R₅ is selected from among an electron pair, —H, and —C(O)—NH₂.

Preferred compounds of formula (I) according to the invention are compounds with R₁, R₂, R₃, R₄, R₅, R₇, R₈, R_(8′), R₉, R_(9′), R₁₀, R₁₁, R_(11′), R₁₂, R₁₃, R_(13′), R₁₄, R₁₅, R_(15′), R₁₆, R₁₇, R₁₈, A, L₁, L₂, Z, Q, and n as herein before or below defined, wherein R₆ is selected from among —H, —CH₃, —C₂H₅, —O—CH₃, —O—C₂H₅, —F, —CF₃, and —OCF₃, and more preferred wherein R₆ is selected from among H, and —O—CH₃, and most preferred wherein R₆ is —H.

Preferred compounds of formula (I) according to the invention are compounds with R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R_(8′), R₉, R_(9′), R₁₀, R₁₁, R_(11′), R₁₂, R₁₃, R_(13′), R₁₄, R₁₅, R_(15′), R₁₆, R₁₇, R₁₈, L₁, L₂, Z, Q, and n as herein before or below defined, wherein A is selected from among a single bond, ═CH—, —CH₂, —O—, and —NH—, and more preferred wherein A is selected from among —O— and —NH—, and most preferred wherein A is —NH—.

Preferred compounds of formula (I) according to the invention are compounds with R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R_(8′), R₉, R_(9′), R₁₀, R₁₁, R_(11′), R₁₂, R₁₃, R_(13′), R₁₄, R₁₅, R_(15′), R₁₆, R₁₇, R₁₈, A, L₁, L₂, Q, and n as herein before or below defined, wherein Z is selected from among C, and N, and more preferred wherein Z is C.

All of the above embodiments under formula (I) have to be understood to optionally be present in form of their individual optical isomers, mixtures of their individual optical isomers, or racemates, as well as in form of their acid addition salts with pharmacologically acceptable acids, as well as in form of their solvates and/or hydrates.

DEFINITIONS

Unless otherwise stated, all the substituents are independent of one another. If for example there might be a plurality of C₁-C₆-alkyl groups as substituents in one group, in the case of three substituents C₁-C₆-alkyl, one may represent methyl, one n-propyl and one tert-butyl.

Within the scope of this application, in the definition of possible substituents, these may also be represented in the form of a structural formula. An asterisk (*) in the structural formula of the substituent is to be understood as being the linking point to the rest of the molecule. Moreover, the atom of the substituent which follows the linking point is referred to as the atom in position number 1. Thus, for example, the groups N-piperidinyl (Piperidin-A), 4-piperidinyl (Piperidin-B), 2-tolyl (Tolyl-C), 3-tolyl (Tolyl-D), and 4-tolyl (Tolyl-E) are shown as follows:

If there is no asterisk (*) in the structural formula of the substituent, each hydrogen atom may be removed from the substituent and the valency thus freed may act as a binding site to the rest of a molecule. Thus, for example, (Tolyl-F) may represent 2-tolyl, 3-tolyl, 4-tolyl, and benzyl

By the term “branched or unbranched, saturated or unsaturated C₁-C₆-carbon chain” it is meant a chain of carbon atoms, which is constituted by six carbon atoms arranged in a row and which can optionally further comprise branches or one or more hetero atoms selected from N, O or S. Said carbon chain can be saturated or unsaturated by comprising double or triple bonds.

By the term “C₁-C₆-alkyl” (including those which are part of other groups) are meant branched and unbranched alkyl groups with 1 to 6 carbon atoms and by the term “C₁-C₄-alkyl” are meant branched and unbranched alkyl groups with 1 to 4 carbon atoms. Alkyl groups with 1 to 4 carbon atoms are preferred. Examples for alkyl groups with 1-6 carbon atoms include: methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, neo-pentyl or hexyl. Optionally the abbreviations Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, t-Bu, etc. may also be used for the above-mentioned groups. Unless stated otherwise, the definitions propyl, butyl, pentyl and hexyl include all the possible isomeric forms of the groups in question. Thus, for example, propyl includes n-propyl and iso-propyl, butyl includes iso-butyl, sec-butyl and tert-butyl etc.

By the term “C₁-C₈-alkylene” (including those which are part of other groups) are meant branched and unbranched alkylene groups with 1 to 8 carbon atoms. By the term “C₂-C₈-alkylene” are meant branched and unbranched alkylene groups with 2 to 8 carbon atoms. By the term “C₂-C₆-alkylene” are meant branched and unbranched alkylene groups with 2 to 6 carbon atoms. By the term “C₁-C₄-alkylene” are meant branched and unbranched alkylene groups with 1 to 4 carbon atoms. By the term “C₁-C₂-alkylene” are meant branched and unbranched alkylene groups with 1 to 2 carbon atoms. By the term “C₀-C₄-alkylene” are meant branched and unbranched alkylene groups with 0 to 4 carbon atoms, thus also a single bond is encompassed. By the term “C₁-C₃-alkylene” are meant branched and unbranched alkylene groups with 1 to 3 carbon atoms. Examples for C₁-C₈-alkylene include: methylene, ethylene, propylene, 1-methylethylene, butylene, 1-methylpropylene, 1,1-dimethylethylene, 1,2-dimethylethylene, pentylene, 1,1-dimethylpropylene, 2,2-dimethylpropylene, 1,2-dimethylpropylene, 1,3-dimethylpropylene, hexylene, heptylene or octylene. Unless stated otherwise, the definitions propylene, butylene, pentylene, hexylene, heptylene and octylene include all the possible isomeric forms of the groups in question with the same number of carbons. Thus, for example, propyl also includes 1-methylethylene and butylene includes 1-methylpropylene, 1,1-dimethylethylene, 1,2-dimethylethylene.

If the carbon chain is to be substituted by a group which together with one or two carbon atoms of the alkylene chain forms a carbocyclic ring with 3, 5 or 6 carbon atoms, this includes the following examples of the rings:

By the term “C₂-C₆-alkenyl” (including those which are part of other groups) are meant branched and unbranched alkenyl groups with 2 to 6 carbon atoms and by the term “C₂-C₄-alkenyl” are meant branched and unbranched alkenyl groups with 2 to 4 carbon atoms, provided that they have at least one double bond. Alkenyl groups with 2 to 4 carbon atoms are preferred. Examples for C₂-C₆-alkenyls include: ethenyl or vinyl, propenyl, butenyl, pentenyl, or hexenyl. Unless stated otherwise, the definitions propenyl, butenyl, pentenyl and hexenyl include all the possible isomeric forms of the groups in question. Thus, for example, propenyl includes 1-propenyl and 2-propenyl, butenyl includes 1-, 2- and 3-butenyl, 1-methyl-1-propenyl, 1-methyl-2-propenyl etc.

By the term “methenylene” is meant a group with 1 carbon atom, provided that it is linked by a single bond as well as on the other side by a double bond:

By the term “C₂-C₈-alkenylene” (including those which are part of other groups) are meant branched and unbranched alkenylene groups with 2 to 8 carbon atoms and by the term “C₂-C₆-alkenylene” are meant branched and unbranched alkylene groups with 2 to 6 carbon atoms. By the term “C₁-C₂-alkenylene” are meant alkenylene groups with 1 to 2 carbon atoms, provided that they have at least one double bond, whereas by the term “C₁-alkenylene” is meant “methenylene”. Examples for C₂-C₈-alkenylenes include: ethenylene, propenylene, 1-methylethenylene, butenylene, 1-methylpropenylene, 1,1-dimethylethenylene, 1,2-dimethylethenylene, pentenylene, 1,1-dimethylpropenylene, 2,2-dimethylpropenylene, 1,2-dimethylpropenylene, 1,3-dimethylpropenylene, hexenylene, heptenylene or octenylene. Unless stated otherwise, the definitions propenylene, butenylene, pentenylene and hexenylene include all the possible isomeric forms of the groups in question with the same number of carbons. Thus, for example, propenyl also includes 1-methylethenylene and butenylene includes 1-methylpropenylene, 1,1-dimethylethenylene, 1,2-dimethylethenylene.

By the term “C₂-C₆-alkynyl” (including those which are part of other groups) are meant branched and unbranched alkynyl groups with 2 to 6 carbon atoms and by the term “C₂-C₄-alkynyl” are meant branched and unbranched alkynyl groups with 2 to 4 carbon atoms, provided that they have at least one triple bond. Examples for C₂-C₆-alkynyls include: ethynyl, propynyl, butynyl, pentynyl or hexynyl. Unless stated otherwise, the definitions propynyl, butynyl, pentynyl and hexynyl include all the possible isomeric forms of the groups in question. Thus for example propynyl includes 1-propynyl and 2-propynyl, butynyl includes 1-, 2-, and 3-butynyl, 1-methyl-1-propynyl, 1-methyl-2-propynyl etc.

By the term “C₂-C₈-alkynylene” (including those which are part of other groups) are meant branched and unbranched alkynylene groups with 2 to 8 carbon atoms and by the term “C₂-C₆-alkynylene” are meant branched and unbranched alkylene groups with 2 to 6 carbon atoms. Examples of C₂-C₈-alkynylenes include: ethynylene, propynylene, 1-methylethynylene, butynylene, 1-methylpropynylene, 1,1-dimethylethynylene, 1,2-dimethylethynylene, pentynylene, 1,1-dimethylpropynylene, 2,2-dimethylpropynylene, 1,2-dimethylpropynylene, 1,3-dimethylpropynylene, hexynylene, heptynylene or octynylene. Unless stated otherwise, the definitions propynylene, butynylene, pentynylene and hexynylene include all the possible isomeric forms of the groups in question with the same number of carbons. Thus for example propynyl also includes 1-methylethynylene and butynylene includes 1-methylpropynylene, 1,1-dimethylethynylene, 1,2-dimethylethynylene.

By the term “ring” are meant carbocycles, which can be saturated, unsaturated or aromatic and which optionally can comprise one or more hetero atoms selected from N, O or S.

By the term “—C₃-C₈-heterocyclyl” are meant three-, four-, five-, six-, or seven-membered, saturated or unsaturated heterocyclic rings which may contain one, two, or three heteroatoms, selected from among oxygen, sulfur, and nitrogen, while the ring may be linked to the molecule through a carbon atom or through a nitrogen atom, if there is one. By the term “—C₅-C₈-heterocyclyl” are meant five-, six-, or seven-membered, saturated or unsaturated heterocyclic rings which may contain one, two, or three heteroatoms, selected from among oxygen, sulfur, and nitrogen, while the ring may be linked to the molecule through a carbon atom or through a nitrogen atom, if there is one. Examples include:

Unless otherwise mentioned, a heterocyclic ring (or “heterocycle”) may be provided with a keto group. Examples include:

By the term “C₃-C₈-cycloalkyl” (including those which are part of other groups) are meant cyclic alkyl groups with 3 to 8 carbon atoms. Likewise, by the term “C₃-C₆-cycloalkyl” are meant cyclic alkyl groups with 3 to 6 carbon atoms. Examples of C₃-C₈-cycloalkyls include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. Unless otherwise stated, the cyclic alkyl groups may be substituted by one or more groups selected from among methyl, ethyl, isopropyl, tert-butyl, hydroxy, fluorine, chlorine, bromine, and iodine.

By the term “aryl” (including those which are part of other groups) are meant aromatic ring systems. By the term “C₅-C₁₀-aryl” (including those which are part of other groups) are meant aromatic ring systems with 5 to 10 carbon atoms. Preferred are “C₆-C₁₀-aryl” groups whereas aromatic rings are meant with 6 to 10 carbon atoms. Examples include: phenyl or naphthyl. Also preferred are “C₅-C₆-aryl” groups whereas aromatic rings are meant with 5 to 6 carbon atoms Unless otherwise stated, the aromatic ring systems may be substituted by one or more groups selected from among methyl, ethyl, iso-propyl, tert-butyl, hydroxy, fluorine, chlorine, bromine and iodine.

By the term “C₅-C₁₀-heteroaryl” (including those which are part of other groups) are meant five- or six-membered heterocyclic aromatic groups or 5-10-membered, bicyclic heteroaryl rings which may contain one, two, or three heteroatoms selected from among oxygen, sulfur, and nitrogen, and contain so many conjugated double bonds that an aromatic system is formed. The following are examples of five- or six- or nine-membered heterocyclic aromatic groups:

Preferred are “C₅-C₆-heteroaryl” groups whereas aromatic rings are meant five- or six-membered heterocyclic aromatic groups. Unless otherwise stated, these heteroaryls may be substituted by one or more groups selected from among methyl, ethyl, isopropyl, tert-butyl, hydroxy, fluorine, chlorine, bromine, and iodine.

When a generic combined groups are used, for example —X—C₁-C₄-alkyl- with X being a functional group such as —CO—, —NH—, —C(OH)— and the like, the functional group X can be located at either of the ends of the —C₁-C₄-alkyl chain.

By the term “spiro-C₃-C₈-cycloalkyl” (spiro) are meant 3-8 membered, spirocyclic rings while the ring is linked to the molecule through a carbon atom. By the term “spiro-C₃-C₈-heterocyclyl” (spiro) are meant 3-8 membered, spirocyclic rings which may contain one, two, or three heteroatoms selected from among oxygen, sulfur, and nitrogen, while the ring may be linked to the molecule through a carbon atom or through a nitrogen atom, if there is one.

Unless otherwise mentioned, a spirocyclic ring may be provided with an oxo, methyl, or ethyl group. Examples include:

“Halogen” within the scope of the present invention denotes fluorine, chlorine, bromine or iodine. Unless stated to the contrary, fluorine, chlorine and bromine are regarded as preferred halogens.

“Linker” within the scope of the present invention denominates a bivalent group or a bond.

The above listed groups and residues can be combined to form more complex structures composed from carbon chains and rings or the like.

Compounds of general formula (I) may have acid groups, chiefly carboxyl groups, and/or basic groups such as e.g. amino functions. Compounds of general formula (I) may therefore occur as internal salts, as salts with pharmaceutically useable inorganic acids such as hydrochloric acid, sulphuric acid, phosphoric acid, sulphonic acid or organic acids (such as for example maleic acid, fumaric acid, citric acid, tartaric acid or acetic acid) or as salts with pharmaceutically useable bases such as alkali or alkaline earth metal hydroxides or carbonates, zinc or ammonium hydroxides or organic amines such as e.g. diethylamine, triethylamine, triethanolamine inter alia.

As mentioned hereinbefore, the compounds of formula (I) may be converted into the salts thereof, particularly for pharmaceutical use, into the physiologically and pharmacologically acceptable salts thereof. These salts may on the one hand be in the form of the physiologically and pharmacologically acceptable acid addition salts of the compounds of formula (I) with inorganic or organic acids. On the other hand, if R is hydrogen, the compound of formula (I) may also be converted by reaction with inorganic bases into physiologically and pharmacologically acceptable salts with alkali or alkaline earth metal cations as counter ion. The acid addition salts may be prepared for example using hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid. It is also possible to use mixtures of the above-mentioned acids. The alkali and alkaline earth metal salts of the compound of formula (I) are preferably prepared using the alkali and alkaline earth metal hydroxides and hydrides thereof, of which the hydroxides and hydrides of the alkaline earth metals, particularly of sodium and potassium, are preferred and sodium and potassium hydroxide are particularly preferred.

If desired, the compounds of general formula (I) may be converted into the salts thereof, particularly, for pharmaceutical use, into the pharmacologically acceptable acid addition salts with an inorganic or organic acid. Suitable acids include for example succinic acid, hydrobromic acid, acetic acid, fumaric acid, maleic acid, methanesulphonic acid, lactic acid, phosphoric acid, hydrochloric acid, sulphuric acid, tartaric acid or citric acid. It is also possible to use mixtures of the above-mentioned acids.

The invention relates to the compounds in question, optionally in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates, in the form of the tautomers as well as in the form of the free bases or the corresponding acid addition salts with pharmacologically acceptable acids—such as for example acid addition salts with hydrohalic acids—for example hydrochloric or hydrobromic acid or organic acids—such as for example oxalic, fumaric, diglycolic or methanesulphonic acid.

The compounds according to the invention may optionally occur as racemates, but they may also be obtained as pure enantiomers/diastereomers.

The invention relates to the compounds in question, optionally in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates, in the form of the tautomers as well as in the form of the free bases or the corresponding acid addition salts with pharmacologically acceptable acids—such as for example acid addition salts with hydrohalic acids—for example hydrochloric or hydrobromic acid or organic acids—such as for example oxalic, fumaric, diglycolic or methanesulphonic acid.

The compounds according to formula (I) according to the invention have the meanings hereinbefore whereas in particular the preferred embodiments defined by R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R_(9′), R₁₀, R₁₁, R_(11′) R₁₂, R₁₃, R_(13′), R₁₄, R₁₅, R_(15′) R₁₆, R₁₇, R₁₈, A, L₁, L₂, Z, Q, and n in each case are independently selected of one another.

Therapeutic Applications

The above exemplary substances have been tested for binding to CCR2 using a binding assay as outlined herein below:

Cell Culture:

THP-1 cells (human acute monocytic leukaemia cells) were cultured under standardized conditions at 37° C. and 5% CO2 in a humidified incubator. THP-1 cells were cultivated in RPMI 1640 medium (Gibco 21875) containing 1% MEM-NEAA (Gibso 11140) 2 mM L-glutamine, 1.5 g/L sodium bicarbonate, 4.5 g/L glucose, 10 mM HEPES and 1.0 mM sodium pyruvate, 90%; 10% fetal calf serum (FCS Gibco 10500-064).

Membranes were prepared from THP-1 cells. THP-1 cells were centrifuged at 300×g at 4° C. for 10 min. The cell pellet was resuspended in Phosphate Buffer Saline (PBS, including 10 μM Pefabloc and a protease inhibitor mix ‘complete’, Boehringer Mannheim (1 tablet/50 ml)), to a concentration of 80 cells/ml. The membrane preparation was performed by disrupting the cells by nitrogen decomposition (at 50 bar, for 1 h) in a “Nitrogen Bombe” (Parr Instrument). Cell debris was removed by centrifugation (800×g at 4° C., 1 min) The supernatant was centrifuged at 80000×g, 4° C. for 30 min to sediment the cell membranes. Usually 50 mg of protein (Bradford assay) were yielded from 1×10E9 cells. The membranes were resuspended in 25 mM HEPES, 25 mM MgCl2, 1 mM CaCl2, 10% Glycerine for storage in aliquots at −80° C. in 25 mM HEPES, 25 mM MgCl2, 1 mM CaCl2, 10% Glycerine and stored at −80° C.

Receptor Membrane Binding Assay:

Perkin Elmer NEX 332 Jod 125 MCP-1, Stock: 2200 Ci/mmol solved in 2000 μl assay buffer, stored at −20° C. THP-1 membrane were adjusted with 25 mM HEPES, pH 7.2; 5 mM MgCl2; 0.5 mM CaCl2; 0.2% BSA assay buffer to a concentration of 2.5 μg/15 μl. Amersham Biosciences PVT-WGA Beads (RPNQ0001) were adjusted with assay buffer to a concentration of 0.24 mg/30 μl. For preparation of the membrane-bead-suspension membranes and beads were incubated for 30 min at RT under rotation (60 rpm) with a ratio of 1:2. Test compounds dissolved in 100% DMSO to a concentration of 10 mM and are further diluted with 100% DMSO to 1 mM. All additional compound dilutions were obtained with assay buffer, final 1% DMSO. Compounds, membrane-bead-suspension and [125I]MCP-1 (ca. 25000 cpm/10 μl) were incubated. Bound radioactivity was determined by scintillation counter after 8 h. Determination of affinity of test compounds (dissociation constant hKi) is calculated by iterative fitting of experimental data using the “easy sys” program, which is based on law of mass action (Schittkowski K. (1994), Numerische Mathematik, Vol. 68, 129-142).

All of the above-referenced examples have been found to have an activity in this assay of 10 μM or less.

CCR2 % ctrl CCR2 % ctrl Example hKi @ 10 μM Example hKi @ 10 μM  1 32 1  15 200 14  2 222 13  16 1904 40  3 204 14  17 302 18  4 1593 43  18 3505 52  5 616 26  19 269 40  6 1928 41  20 303 24  7 306 16  21 2660 51  8 1023 36  22 466 24  9 974 32  23 169 7  10 650 27  24 4029 58  11 1710 38  25 2406 47  12 664 29  26 914 30  13 1332 42  27 620 25  14 387 22  28 4176 58  29 2097 40  59 55 5  30 446 18  60 44 5  31 790 28  61 46 2  32 37 2  62 38 3  33 22 0  63 54 7  34 62 4  64 65 8  35 24 5  65 176 8  36 10 1  66 138 8  37 11 4  67 1423 27  38 69 13  68 98 7  39 36 2  69 63 7  40 174 9  70 80 6  41 11 6  71 117 12  42 433 16  72 81 7  43 566 17  73 38 2  44 1639 27  74 71 2  45 501 17  75 67 7  46 225 12  76 132 12  47 222 14  77 650 27  48 1778 26  78 740 28  49 97 7  79 89 10  50 928 22  80 53 7  51 290 13  81 52 8  52 175 12  82 43 4  53 18 4  83 43 3  54 356 13  84 69 4  55 200 17  85 55 13  56 127 8  86 39 3  57 93 10  87 78 9  58 336 12  88 58 6  89 770 29 119 1033 37  90 127 10 120 499 30  91 236 23 121 147 15  92 175 14 122 415 23  93 123 6 123 542 26  94 211 8 124 361 20  95 170 2 125 446 25  96 939 21 126 399 23  97 665 17 127 665 35  98 214 2 128 445 26  99 1826 32 129 336 21 100 395 18 130 4266 50 101 986 35 131 55 6 102 224 15 132 672 31 103 1605 30 133 205 15 104 617 31 134 399 23 105 687 31 135 888 19 106 405 13 136 773 14 107 232 12 137 634 14 108 627 20 138 145 6 109 213 11 139 443 9 110 527 28 140 692 16 111 464 27 141 422 7 112 378 21 142 529 8 113 3306 46 143 422 8 114 62 8 144 91 7 115 847 33 145 181 17 116 198 16 146 3 7 117 285 19 147 40 8 118 2162 41 148 119 4 149 41 10 179 1637 42 150 12 3 189 4812 60 151 14 7 181 3607 58 152 44 7 182 2991 53 153 27 1 183 426 45 154 123 15 184 908 30 155 76 8 185 4209 53 156 18 8 186 78 8 157 1147 23 187 256 15 158 6 0 188 3934 53 159 25 4 189 170 13 160 43 3 190 783 27 161 1996 30 191 519 20 162 3798 43 192 1446 37 163 1560 32 193 1536 35 164 353 15 194 491 25 165 222 15 195 141 14 166 227 16 196 666 19 167 246 16 197 33 4 168 51 9 198 58 1 169 2287 54 199 534 9 170 705 31 200 108 5 171 356 16 201 101 6 172 736 28 202 292 7 173 89 6 203 641 11 174 2718 53 204 123 6 175 434 14 205 135 11 176 648 31 206 44 3 177 1252 43 207 1180 35 178 27 0 208 99 7 209 177 7 239 2319 33 210 83 0 240 104 7 211 140 5 241 522 21 212 731 24 242 516 21 213 430 14 243 1615 40 214 711 20 244 366 24 215 2146 42 245 555 15 216 4283 59 246 306 2 217 4326 54 247 149 6 218 281 8 248 576 17 219 476 22 249 3249 36 220 979 27 250 1263 32 221 172 12 251 439 75 222 1306 31 252 38 6 223 244 14 253 350 17 224 1230 35 254 101 11 225 21 0 255 33 5 226 1170 36 256 438 25 227 333 22 257 186 14 228 331 16 258 64 4 229 1133 39 259 277 16 230 1845 45 260 493 20 231 215 15 261 120 8 232 924 34 262 224 13 233 194 8 263 1968 27 234 401 19 264 41 3 235 460 26 265 462 23 236 175 14 266 149 237 133 9 267 487 20 238 239 14 268 119 5 228a 1564 9 228e 3720 40 228b 2 4 228f 15 1 228c 29 0 228g 169 6 228d 91 1 228h 5 0 269 2340 36 285 1306 35 270 179 9 286 965 19 271 1608 15 287 2547 33 272 155 8 288 738 13 273 1435 27 289 1667 34 274 4421 48 290 1601 28 275 593 19 291 3123 32 276 1842 23 292 136 15 277 1376 34 293 717 27 278 1078 32 294 230 16 279 192 9 295 140 0 280 1435 32 296 69 3 281 1012 24 297 164 10 282 1527 39 298 599 17 283 4421 48 299 70 6 284 1514 42 300 136 8 275a 29 0 275c 2932 38 275b 26 3 275d 318 10 Example hki Example hki 228go 54 159e 28 228gp 1354 159f 14 228ga 23 159g 15 228gb 3828 159h 39 228gc 561 159i 24 228gd 1094 159k 22 228ge 37 159l 22 228gf 145 159m 9 228gg 1026 159n 233 228gh 4066 159o 12 228gi 1101 159p 7 228gj 55 159q 10 228gk 44 159r 2578 228gl 537 159s 1314 228gm 28 159t 1202 228gn 333 159u 29 275da 4 159w 9 275db 33 159y 169 275dc 11 159x 147 275dd 40 159z 11 275de 16 159aa 18 275df 15 159ba 11 275dg 12 159ca 3 275dh 3 159da 5 275di 1 159ea 7 275dj 4 159fa 35 159a 10 159ga 28 159b 7 159ha 27 159c 13 159ia 17 159d 15 159ja 18 159ka 19 159pb 10 159la 19 159qb 69 159ma 20 159rb 54 159na 21 159sb 21 159oa 29 159tb 13 159pa 32 159ub 18 159qa 19 159wb 16 159ra 22 159yb 15 159sa 22 159xb 6 159ta 27 159zb 15 159ua 23 159ac 5936 159wa 33 159bc 3492 159ya 18 159cc 10 159xa 21 159dc 38 159za 6 159ec 961 159ab 27 159fc 13 159bb 48 159gc 26 159cb 39 228ha 32 159db 16 301 22 159eb 72 302 32 159fb 199 275dk 17 159gb 39 275dl 372 159hb 20 159ib 15 159jb 39 159kb 24 159lb 12 159mb 14 159nb 88 159ob 118

Based on the ability of the substances described by formula (I) to effectively bind to CCR2 a range of therapeutic applications can be envisaged. The present invention provides a method for modulating or treating at least one MCP-1 related disease, in a cell, tissue, organ, animal, or patient, as known in the art or as described herein, using at least one CCR2 antagonist of the present invention. The present invention also provides a method for modulating or treating at least one MCP-1 related disease, in a cell, tissue, organ, animal, or patient including, but not limited to, at least one of malignant disease, metabolic disease, an immune or inflammatory related disease, a cardiovascular disease, an infectious disease, or a neurologic disease. Such conditions are selected from, but not limited to, diseases or conditions mediated by cell adhesion and/or angiogenesis. Such diseases or conditions include an immune disorder or disease, a cardiovascular disorder or disease, an infectious, malignant, and/or neurologic disorder or disease, or other known or specified MCP-1 related conditions. In particular, the CCR2 antagonists are useful for the treatment of diseases that involve inflammation such as COPD, angiogenesis such as disease of the eye and neoplastic disease, tissue remodeling such as restenosis, and proliferation of certain cells types particularly epithelial and squamous cell carcinomas. Particular indications include use in the treatment of atherosclerosis, restenosis, cancer metastasis, rheumatoid arthritis, diabetic retinopathy and macular degeneration. The antagonists may also be useful in the treatment of various fibrotic diseases such as idiopathic pulmonary fibrosis, diabetic nephropathy, hepatitis, and cirrhosis. Thus, the present invention provides a method for modulating or treating at least one CCR2 related disease, in a cell, tissue, organ, animal, or patient, as known in the art or as described herein, using at least one CCR2 antagonist of the present invention. Particular indications are discussed below:

Pulmonary Diseases

The present invention also provides a method for modulating or treating at least one malignant disease in a cell, tissue, organ, animal or patient, including, but not limited to, at least one of: pneumonia; lung abscess; occupational lung diseases caused be agents in the form or dusts, gases, or mists; asthma, bronchiolitis fibrosa obliterans, respiratory failure, hypersensitivity diseases of the lungs including hypersensitivity pneumonitis (extrinsic allergic alveolitis), allergic bronchopulmonary aspergillosis, and drug reactions; adult respiratory distress syndrome (ARDS), Goodpasture's Syndrome, chronic obstructive airway disorders (COPD), idiopathic interstitial lung diseases such as idiopathic pulmonary fibrosis and sarcoidosis, desquamative interstitial pneumonia, acute interstitial pneumonia, respiratory bronchiolitis-associated interstitial lung disease, idiopathic bronchiolitis obliterans with organizing pneumonia, lymphocytic interstitial pneumonitis, Langerhans' cell granulomatosis, idiopathic pulmonary hemosiderosis; acute bronchitis, pulmonary alveolar, proteinosis, bronchiectasis, pleural disorders, atelectasis, cystic fibrosis, and tumors of the lung, and pulmonary embolism.

Malignant Diseases

The present invention also provides a method for modulating or treating at least one malignant disease in a cell, tissue, organ, animal or patient, including, but not limited to, at least one of: leukemia, acute leukemia, acute lymphoblastic leukemia (ALL), B-cell, T-cell or FAB ALL, acute myeloid leukemia (AML), chromic myelocytic leukemia (CML), chronic lymphocytic leukemia (CLL), hairy cell leukemia, myelodyplastic syndrome (MDS), a lymphoma, Hodgkin's disease, a malignant lymphoma, non-hodgkin's lymphoma, Burkitt's lymphoma, multiple myeloma, Kaposi's sarcoma, colorectal carcinoma, pancreatic carcinoma, renal cell carcinoma, breast cancer, nasopharyngeal carcinoma, malignant histiocytosis, paraneoplastic syndrome/hypercalcemia of malignancy, solid tumors, adenocarcinomas, squamous cell carcinomas, sarcomas, malignant melanoma, particularly metastatic melanoma, hemangioma, metastatic disease, cancer related bone resorption, cancer related bone pain, and the like.

Immune Related Diseases

The present invention also provides a method for modulating or treating at least one immune related disease, in a cell, tissue, organ, animal, or patient including, but not limited to, at least one of rheumatoid arthritis, juvenile rheumatoid arthritis, systemic onset juvenile rheumatoid arthritis, psoriatic arthritis, ankylosing spondilitis, gastric ulcer, seronegative arthropathies, osteoarthritis, inflammatory bowel disease, ulcerative colitis, systemic lupus erythematosis, antiphospholipid syndrome, iridocyclitisluveitisloptic neuritis, idiopathic pulmonary fibrosis, systemic vasculitis/wegener's granulomatosis, sarcoidosis, orchitislvasectomy reversal procedures, allergiclatopic diseases, asthma, allergic rhinitis, eczema, allergic contact dermatitis, allergic conjunctivitis, hypersensitivity pneumonitis, transplants, organ transplant rejection, graft-versus-host disease, systemic inflammatory response syndrome, sepsis syndrome, gram positive sepsis, gram negative sepsis, culture negative sepsis, fungal sepsis, neutropenic fever, urosepsis, meningococcemia, traumalhemo˜˜hage, burns, ionizing radiation exposure, acute pancreatitis, adult respiratory distress syndrome, rheumatoid arthritis, alcohol-induced hepatitis, chronic inflammatory pathologies, sarcoidosis, Crohn's pathology, sickle cell anemia, diabetes, nephrosis, atopic diseases, hypersensitity reactions, allergic rhinitis, hay fever, perennial rhinitis, conjunctivitis, endometriosis, asthma, urticaria, systemic anaphalaxis, dermatitis, pernicious anemia, hemolytic diseases, thrombocytopenia, graft rejection of any organ or tissue, kidney transplant rejection, heart transplant rejection, liver transplant rejection, pancreas transplant rejection, lung transplant rejection, bone marrow transplant (BMT) rejection, skin allograft rejection, cartilage transplant rejection, bone graft rejection, small bowel transplant rejection, fetal thymus implant rejection, parathyroid transplant rejection, xenograft rejection of any organ or tissue, allograft rejection, anti-receptor hypersensitivity reactions, Graves disease, Raynoud's disease, type B insulin-resistant diabetes, asthma, myasthenia gravis, antibody-meditated cytotoxicity, type IU hypersensitivity reactions, systemic lupus erythematosus, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes syndrome), polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes syndrome, antiphospholipid syndrome, pemphigus, scleroderma, mixed connective tissue disease, idiopathic Addison's disease, diabetes mellitus, chronic active hepatitis, primary billiary cirrhosis, vitiligo, vasculitis, post-MI cardiotomy syndrome, type IV hypersensitivity, contact dermatitis, hypersensitivity pneumonitis, allograft rejection, granulomas due to intracellular organisms, drug sensitivity, metabolic/idiopathic, Wilson's disease, hemachromatosis, alpha-1-antitrypsin deficiency, diabetic retinopathy, hashimoto's thyroiditis, osteoporosis, hypothalamic-pituitary-adrenal axis evaluation, primary biliary cirrhosis, thyroiditis, encephalomyelitis, cachexia, cystic fibrosis, neonatal chronic lung disease, chronic obstructive pulmonary disease (COPD), familial hematophagocytic lymphohistiocytosis, dermatologic conditions, psoriasis, alopecia, nephrotic syndrome, nephritis, glomerular nephritis, acute renal failure, hemodialysis, uremia, toxicity, preeclampsia, OKT3 therapy, anti-CD3 therapy, cytokine therapy, chemotherapy, radiation therapy (e.g., including but not limited toasthenia, anemia, cachexia, and the like), chronic salicylate intoxication, and the like.

Cardiovascular Diseases

The present invention also provides a method for modulating or treating at least one cardiovascular disease in a cell, tissue, organ, animal, or patient, including, but not limited to, at least one of cardiac 25 stun syndrome, myocardial infarction, congestive heart failure, stroke, ischemic stroke, hemorrhage, arteriosclerosis, atherosclerosis, restenosis, diabetic arteriosclerotic disease, hypertension, arterial hypertension, renovascular hypertension, syncope, shock, syphilis of the cardiovascular system, heart failure, cor pulmonale, primary pulmonary hypertension, cardiac arrhythmias, atrial ectopic beats, atrial flutter, atrial fibrillation (sustained or paroxysmal), post perfusion syndrome, cardiopulmonary bypass inflammation response, chaotic or multifocal atrial tachycardia, regular narrow QRS tachycardia, specific arrythmias, ventricular fibrillation, His bundle arrythmias, atrioventricular block, bundle branch block, myocardial ischemic disorders, coronary artery disease, angina pectoris, myocardial infarction, cardiomyopathy, dilated congestive cardiomyopathy, restrictive cardiomyopathy, valvular heart diseases, endocarditis, pericardial disease, cardiac tumors, aordic and peripheral aneuryisms, aortic dissection, inflammation of the aorta, occlusion of the abdominal aorta and its branches, peripheral vascular disorders, occlusive arterial disorders, peripheral atherosclerotic disease, thromboangiitis obliterans, functional peripheral arterial disorders, Raynaud's phenomenon and disease, acrocyanosis, erythromelalgia, venous diseases, venous thrombosis, varicose veins, arteriovenous fistula, lymphederma, lipedema, unstable angina, reperfusion injury, post pump syndrome, ischemia-reperfusion injury, and the like. Such a method can optionally comprise administering an effective amount of a composition or pharmaceutical composition comprising at least one CCR2 antagonist to a cell, tissue, organ, animal or patient in need of such modulation, treatment or therapy.

Neurologic Diseases

The present invention also provides a method for modulating or treating at least one neurologic disease in a cell, tissue, organ, animal or patient, including, but not limited to, at least one of: Neuropathic pain such as low back pain, hip pain, leg pain, non-herpetic neuralgia, post herpetic neuralgia, diabetic neuropathy, nerve injury-induced pain, acquired immune deficiency syndrome (AIDS) related neuropathic pain, head trauma, toxin and chemotherapy caused nerve injuries, phantom limb pain, multiple sclerosis, root avulsions, painful traumatic mononeuropathy, painful polyneuropathy, thalamic pain syndrome, post-stroke pain, central nervous system injury, post surgical pain, carpal tunnel syndrome, trigeminal neuralgia, post mastectomy syndrome, postthoracotomy syndrome, stump pain, repetitive motion pain, neuropathic pain associated hyperalgesia and allodynia, alcoholism and other drug-induced pain; neurodegenerative diseases, multiple sclerosis, migraine headache, AIDS dementia complex, demyelinating diseases, such as multiple sclerosis and acute transverse myelitis; extrapyramidal and cerebellar disorders' such as lesions of the corticospinal system; disorders of the basal ganglia or cerebellar disorders; hyperkinetic movement disorders such as Huntington's Chorea and senile chorea; drug-induced movement disorders, such as those induced by drugs which block CNS dopamine receptors; hypokinetic movement disorders, such as Parkinson's disease; Progressive supra-nucleo Palsy; structural lesions of the cerebellum; spinocerebellar degenerations, such as spinal ataxia, Friedreich's ataxia, cerebellar cortical degenerations, multiple systems degenerations (Mencel, Dejerine-Thomas, Shi-Drager, and Machado-Joseph); systemic disorders (Refsum's disease, abetalipoprotemia, ataxia, telangiectasia, and mitochondrial multi.system disorder); demyelinating core disorders, such as multiple sclerosis, acute transverse myelitis; and disorders of the motor unit′ such as neurogenic muscular atrophies (anterior horn cell degeneration, such as amyotrophic lateral sclerosis, infantile spinal muscular atrophy and juvenile spinal muscular atrophy); Alzheimer's disease; Down's Syndrome in middle age; Diffuse Lewy body disease; Senile Dementia of Lewy body type; Wernicke-Korsakoff syndrome; chronic alcoholism; Creutzfeldt-Jakob disease; Subacute sclerosing panencephalitis, Hallerrorden-Spatz disease; and Dementia pugilistica, and the like.

Fibrotic Conditions

In addition to the above described conditions and diseases, the present invention also provides a method for modulating or treating fibrotic conditions of various etiologies such as liver fibrosis (including but not limited to alcohol-induced cirrhosis, viral-induced cirrhosis, autoimmune-induced hepatitis); lung fibrosis (including but not limited to scleroderma, idiopathic pulmonary fibrosis); kidney fibrosis (including but not limited to scleroderma, diabetic nephritis, glomerular pehpritis, lupus nephritis); dermal fibrosis (including but not limited to scleroderma, hypertrophic and keloid scarring, burns); myelofibrosis; Neurofibromatosis; fibroma; intestinal fibrosis; and fibrotic adhesions resulting from surgical procedures.

The present invention also provides a method for modulating or treating at least one wound, trauma or tissue injury or chronic condition resulting from or related thereto, in a cell, tissue, organ, animal or patient, including, but not limited to, at least one of: bodily injury or a trauma associated with surgery including thoracic, abdominal, cranial, or oral surgery; or wherein the wound is selected from the group consisting of aseptic wounds, contused wounds, incised wounds, lacerated wounds, non-penetrating wounds, open wounds, penetrating wounds, perforating wounds, puncture wounds, septic wounds, infarctions and subcutaneous wounds; or wherein the wound is selected from the group consisting of ischemic ulcers, pressure sores, fistulae, severe bites, thermal burns and donor site wounds; or wherein the wound is an aphthous wound, a traumatic wound or a herpes associated wound. Donor site wounds are wounds which e.g. occur in connection with removal of hard tissue from one part of the body to another part of the body e.g. in connection with transplantation. The wounds resulting from such operations are very painful and an improved healing is therefore most valuable. Wound fibrosis is also amenable to CCR2 antagonist therapy as the first cells to invade the wound area are neutrophils followed by monocytes which are activated by macrophages. Macrophages are believed to be essential for efficient wound healing in that they also are responsible for phagocytosis of pathogenic organisms and a clearing up of tissue debris. Furthermore, they release numerous factors involved in subsequent events of the healing process. The macrophages attract fibroblasts which start the production of collagen. Almost all tissue repair processes include the early connective tissue formation, a stimulation of this and the subsequent processes improve tissue healing, however, overproduction of connective tissue and collagen can lead to a fibrotic tissue characterized as inelastic and hypoxic. The CCR2 antagonist of the invention can be used in methods for modulating, treating or preventing such sequalae of wound healing.

Other Therapeutic Uses of CCR2 Antagonists

The present invention also provides a method for modulating or treating at least one infectious disease in a cell, tissue, organ, animal or patient, including, but not limited to, at least one of:

acute or chronic bacterial infection, acute and chronic parasitic or infectious processes, including bacterial, viral and fungal infections, HIV infection, HIV neuropathy, meningitis, hepatitis (A, B or C, or the like), septic arthritis, peritonitis, pneumonia, epiglottitis, e. coli 0157:h7, hemolytic uremic syndrome/thrombolytic thrombocytopenic purpura, malaria, dengue hemorrhagic fever, leishmaniasis, leprosy, toxic shock syndrome, streptococcal myositis, gas gangrene, mycobacterium tuberculosis, mycobacterium avium intracellulare, pneumocystis carinii pneumonia, pelvic inflammatory disease, orchitislepidydimitis, legionella, lyme disease, influenza a, epstein-barr virus, vital-associated hemaphagocytic syndrome, vital encephalitisiaseptic meningitis, and the like.

Any method of the present invention can comprise administering an effective amount of a composition or pharmaceutical composition comprising at least one CCR2 antagonist to a cell, tissue, organ, animal or patient in need of such modulation, treatment or therapy.

Besides being useful for human treatment, these compounds are also useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, and the like.

Combinations The compounds of formula I may be used on their own or in conjunction with other active substances of formula I according to the invention. If desired the compounds of formula I may also be used in combination with other pharmacologically active substances. It is preferable to use for this purpose active substances selected for example from among betamimetics, anticholinergics, corticosteroids, other PDE4-inhibitors, LTD4-antagonists, EGFR-inhibitors, MRP4-inhibitors, dopamine agonists, H1-antihistamines, PAF-antagonists and PI3-kinase inhibitors or double or triple combinations thereof, such as for example combinations of compounds of formula I with one or two compounds selected from among

-   -   betamimetics, corticosteroids, PDE4-inhibitors, EGFR-inhibitors         and LTD4-antagonists,     -   anticholinergics, betamimetics, corticosteroids,         PDE4-inhibitors, EGFR-inhibitors and LTD4-antagonists,     -   PDE4-inhibitors, corticosteroids, EGFR-inhibitors and         LTD4-antagonists     -   EGFR-inhibitors, PDE4-inhibitors and LTD4-antagonists     -   EGFR-inhibitors and LTD4-antagonists     -   CCR3-inhibitors, iNOS-inhibitors (inducible nitric oxide         synthase-inhibitors), (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin         (hereinafter referred to as “BH4”) and the derivatives thereof         as mentioned in WO 2006/120176 and SYK-inhibitors (spleen         tyrosine kinase-inhibitors)     -   anticholinergics, betamimetics, corticosteroids, PDE4-inhibitors         and MRP4-inhibitors.

The invention also encompasses combinations of three active substances, each selected from one of the above-mentioned categories of compounds.

The betamimetics used are preferably compounds selected from among albuterol, bambuterol, bitolterol, broxaterol, carbuterol, clenbuterol, fenoterol, formoterol, arformoterol, zinterol, hexoprenaline, ibuterol, isoetharine, isoprenaline, levosalbutamol, mabuterol, meluadrine, metaproterenol, orciprenaline, pirbuterol, procaterol, reproterol, rimiterol, ritodrine, salmeterol, salmefamol, soterenol, sulphonterol, tiaramide, terbutaline, tolubuterol, CHF-1035, HOKU-81, KUL-1248, 3-(4-{6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}-butyl)-benzyl-sulphonamide, 5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one, 4-hydroxy-7-[2-{[2-{[3-(2-phenylethoxy)propyl]sulphonyl}ethyl]-amino}ethyl]-2(3H)-benzothiazolone, 1-(2-fluoro-4-hydroxyphenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol, 1-[3-(4-methoxybenzyl-amino)-4-hydroxyphenyl]-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminophenyl)-2-methyl-2-propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-methyl-2-propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-methyl-2-propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-1,2,4-triazol-3-yl]-2-methyl-2-butylamino}ethanol, 5-hydroxy-8-(1-hydroxy-2-isopropylaminobutyl)-2H-1,4-benzoxazin-3-(4H)-one, 1-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-tert.-butylamino)ethanol, 6-hydroxy-8-{1-hydroxy-2-[2-(4-methoxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one, 6-hydroxy-8-{1-hydroxy-2-[2-(4-phenoxy-acetate ethyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one, 6-hydroxy-8-{1-hydroxy-2-[2-(4-phenoxy-acetic acid)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one, 8-{2-[1,1-dimethyl-2-(2,4,6-trimethylphenyl)-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one, 6-hydroxy-8-{1-hydroxy-2-[2-(4-hydroxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one, 6-hydroxy-8-{1-hydroxy-2-[2-(4-isopropyl-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one, 8-{2-[2-(4-ethyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one, 8-{2-[2-(4-ethoxy-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one, 4-(4-{2-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-2-methyl-propyl}-phenoxy)-butyric acid, 8-{2-[2-(3,4-difluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one and 1-(4-ethoxy-carbonylamino-3-cyano-5-fluorophenyl)-2-(tert.-butylamino)ethanol, optionally in the form of the racemates, enantiomers, diastereomers thereof and optionally in the form of the pharmacologically acceptable acid addition salts, solvates or hydrates thereof.

Preferably the beta mimetics are selected from among bambuterol, bitolterol, carbuterol, clenbuterol, fenoterol, formoterol, hexoprenaline, ibuterol, pirbuterol, procaterol, reproterol, salmeterol, sulphonterol, terbutaline, tolubuterol, 3-(4-{6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}-butyl)-benzenesulphonamide, 5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one, 4-hydroxy-7-[2-{[2-{[3-(2-phenylethoxy)propyl]sulphonyl}ethyl]-amino}ethyl]-2(3H)-benzothiazolone, 1-(2-fluoro-4-hydroxyphenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol, 1-[3-(4-methoxybenzyl-amino)-4-hydroxyphenyl]-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminophenyl)-2-methyl-2-propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-methyl-2-propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-methyl-2-propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-1,2,4-triazol-3-yl]-2-methyl-2-butylamino}ethanol, 5-hydroxy-8-(1-hydroxy-2-isopropylaminobutyl)-2H-1,4-benzoxazin-3-(4H)-one, 1-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-tert.-butylamino)ethanol, 6-hydroxy-8-{1-hydroxy-2-[2-(4-methoxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one, 6-hydroxy-8-{1-hydroxy-2-[2-(4-phenoxy-acetate ethyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one, 6-hydroxy-8-{1-hydroxy-2-[2-(4-phenoxy-acetic acid)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one, 8-{2-[1,1-dimethyl-2-(2,4,6-trimethylphenyl)-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one, 6-hydroxy-8-{1-hydroxy-2-[2-(4-hydroxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one, 6-hydroxy-8-{1-hydroxy-2-[2-(4-isopropyl-phenyl)-1,1dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one, 8-{2-[2-(4-ethyl-phenyl)-1,1-dimethyl-ethyl amino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one, 8-{2-[2-(4-ethoxy-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one, 4-(4-{2-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-2-methyl-propyl}-phenoxy)-butyric acid, 8-{2-[2-(3,4-difluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one and 1-(4-ethoxycarbonylamino-3-cyano-5-fluorophenyl)-2-(tert.-butylamino)ethanol, optionally in the form of the racemates, enantiomers, diastereomers thereof and optionally in the form of the pharmacologically acceptable acid addition salts, solvates or hydrates thereof.

Particularly preferred betamimetics are selected from among fenoterol, formoterol, salmeterol, 3-(4-{6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}-butyl)-benzenesulphonamide, 5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one, 1-[3-(4-methoxybenzyl-amino)-4-hydroxyphenyl]-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminophenyl)-2-methyl-2-propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-methyl-2-propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-methyl-2-propylamino]ethanol, 6-hydroxy-8-{1-hydroxy-2-[2-(4-methoxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one, 6-hydroxy-8-{1-hydroxy-2-[2-(4-phenoxy-acetate ethyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one, 6-hydroxy-8-{1-hydroxy-2-[2-(4-phenoxy-acetic acid)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one, 8-{2-[1,1-dimethyl-2-(2,4,6-trimethylphenyl)-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one, 6-hydroxy-8-{1-hydroxy-2-[2-(4-hydroxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one, 6-hydroxy-8-{1-hydroxy-2-[2-(4-isopropyl-phenyl)-1,1dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one, 8-{2-[2-(4-ethyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one, 8-{2-[2-(4-ethoxy-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one, 4-(4-{2-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-2-methyl-propyl}-phenoxy)-butyric acid, 8-{2-[2-(3,4-difluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one and 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-1,2,4-triazol-3-yl]-2-methyl-2-butylamino}ethanol, optionally in the form of the racemates, enantiomers, diastereomers thereof and optionally in the form of the pharmacologically acceptable acid addition salts, solvates or hydrates thereof.

Of these betamimetics those which are particularly preferred according to the invention are formoterol, salmeterol, 3-(4-{6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}-butyl)-benzenesulphonamide, 6-hydroxy-8-{1-hydroxy-2-[2-(4-methoxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one, 6-hydroxy-8-{1-hydroxy-2-[2-(ethyl 4-phenoxy-acetate)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one, 6-hydroxy-8-{1-hydroxy-2-[2-(4-phenoxy-acetic acid)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one, 8-{2-[1,1-dimethyl-2-(2,4,6-trimethylphenyl)-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one, 6-hydroxy-8-{1-hydroxy-2-[2-(4-hydroxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one, 6-hydroxy-8-{1-hydroxy-2-[2-(4-isopropyl-phenyl)-1,1dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one, 8-{2-[2-(4-ethyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one, 8-{2-[2-(4-ethoxy-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one, 4-(4-{2-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-2-methyl-propyl}-phenoxy)-butyric acid, 8-{2-[2-(3,4-difluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one and 5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one, optionally in the form of the racemates, enantiomers, diastereomers thereof and optionally in the form of the pharmacologically acceptable acid addition salts, solvates or hydrates thereof.

According to the invention the acid addition salts of the betamimetics are preferably selected from among hydrochloride, hydrobromide, hydriodide, hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate, hydrobenzoate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonat, preferably hydrochloride, hydrobromide, hydrosulphate, hydrophosphate, hydrofumarate and hydromethanesulphonate. Of the above-mentioned acid addition salts the salts of hydrochloric acid, methanesulphonic acid, benzoic acid and acetic acid are particularly preferred according to the invention.

The anticholinergics used are preferably compounds selected from among the tiotropium salts, oxitropium salts, flutropium salts, ipratropium salts, glycopyrronium salts, trospium salts, tropenol 2,2-diphenylpropionate methobromide, scopine 2,2-diphenylpropionate methobromide, scopine 2-fluoro-2,2-diphenylacetate methobromide, tropenol 2-fluoro-2,2-diphenylacetate methobromide, tropenol 3,3′,4,4′-tetrafluorobenzilate methobromide, scopine 3,3′,4,4′-tetrafluorobenzilate methobromide, tropenol 4,4′-difluorobenzilate methobromide, scopine 4,4′-difluorobenzilate methobromide, tropenol 3,3′-difluorobenzilate methobromide, -scopine 3,3′-difluorobenzilate methobromide, tropenol 9-hydroxy-fluorene-9-carboxylate-methobromide, tropenol 9-fluoro-fluorene-9-carboxylate-methobromide, scopine 9-hydroxy-fluoren-9-carboxylate methobromide, scopine 9-fluoro-fluorene-9-carboxylate methobromide, tropenol 9-methyl-fluorene-9-carboxylate methobromide, scopine 9-methyl-fluorene-9-carboxylate methobromide, cyclopropyltropine benzilate methobromide, cyclopropyltropine 2,2-diphenylpropionate methobromide, cyclopropyltropine 9-hydroxy-xanthene-9-carboxylate methobromide, cyclopropyltropine 9-methyl-fluorene-9-carboxylate methobromide, cyclopropyltropine 9-methyl-xanthene-9-carboxylate methobromide, cyclopropyltropine 9-hydroxy-fluorene-9-carboxylate methobromide, methyl-cyclopropyltropine 4,4′-difluorobenzilate methobromide, tropenol 9-hydroxy-xanthene-9-carboxylate-methobromide, scopine 9-hydroxy-xanthene-9-carboxylate methobromide, tropenol 9-methyl-xanthene-9-carboxylate methobromide, scopine 9-methyl-xanthene-9-carboxylate methobromide, tropenol 9-ethyl-xanthene-9-carboxylate methobromide, tropenol 9-difluoromethyl-xanthene-9-carboxylate methobromide, scopine 9-hydroxymethyl-xanthene-9-carboxylate methobromide, optionally in the form of the solvates or hydrates thereof.

In the above-mentioned salts the cations tiotropium, oxitropium, flutropium, ipratropium, glycopyrronium and trospium are the pharmacologically active ingredients. As anions, the above-mentioned salts may preferably contain chloride, bromide, iodide, sulphate, phosphate, methanesulphonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate or p-toluenesulphonate, while chloride, bromide, iodide, sulphate, methanesulphonate or p-toluenesulphonate are preferred as counter-ions. Of all the salts, the chlorides, bromides, iodides and methanesulphonate are particularly preferred.

Of particular importance is tiotropium bromide. In the case of tiotropium bromide the pharmaceutical combinations according to the invention preferably contain it in the form of the crystalline tiotropium bromide monohydrate, which is known from WO 02/30928. If the tiotropium bromide is used in anhydrous form in the pharmaceutical combinations according to the invention, it is preferable to use anhydrous crystalline tiotropium bromide, which is known from WO 03/000265.

Corticosteroids used here are preferably compounds selected from among prednisolone, prednisone, butixocortpropionate, flunisolide, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide, rofleponide, dexamethasone, betamethasone, deflazacort, RPR-106541, NS-126, (S)-fluoromethyl 6,9-difluoro-17-[(2-furanylcarbonyl)oxy]-11-hydroxy-16-methyl-3-oxo-androsta-1,4-diene-17-carbothionate and

(S)-(2-oxo-tetrahydro-furan-3S-yl) 6,9-difluoro-11-hydroxy-16-methyl-3-oxo-17-propionyloxy-androsta-1,4-diene-17-carbothionate, optionally in the form of the racemates, enantiomers or diastereomers thereof and optionally in the form of the salts and derivatives, solvates and/or hydrates thereof.

Particularly preferred is the steroid selected from among flunisolide, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide, rofleponide, dexamethasone, NS-126, (S)-fluoromethyl 6,9-difluoro-17-[(2-furanylcarbonyl)oxy]-11-hydroxy-16-methyl-3-oxo-androsta-1,4-diene-17-carbothionate and (S)-(2-oxo-tetrahydro-furan-3S-yl) 6,9-difluoro-11-hydroxy-16-methyl-3-oxo-17-propionyloxy-androsta-1,4-diene-17-carbothionate, optionally in the form of the racemates, enantiomers or diastereomers thereof and optionally in the form of the salts and derivatives, solvates and/or hydrates thereof.

Particularly preferred is the steroid selected from among budesonide, fluticasone, mometasone, ciclesonide and (S)-fluoromethyl 6,9-difluoro-17-[(2-furanylcarbonyl)oxy]-11-hydroxy-16-methyl-3-oxo-androsta-1,4-diene-17-carbothionate, optionally in the form of the racemates, enantiomers or diastereomers thereof and optionally in the form of the salts and derivatives, solvates and/or hydrates thereof.

Any reference to steroids includes a reference to any salts or derivatives, hydrates or solvates thereof which may exist. Examples of possible salts and derivatives of the steroids may be: alkali metal salts, such as for example sodium or potassium salts, sulphobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogen phosphates, palmitates, pivalates or furoates thereof.

Other PDE4 inhibitors which may be used are preferably compounds selected from among enprofyllin, theophyllin, roflumilast, ariflo (cilomilast), tofimilast, pumafentrin, lirimilast, arofyllin, atizoram, D-4396 (Sch-351591), AWD-12-281 (GW-842470), NCS-613, CDP-840, D-4418, PD-168787, T-440, T-2585, V-11294A, C1-1018, CDC-801, CDC-3052, D-22888, YM-58997, Z-15370, N-(3,5-dichloro-1-oxo-pyridin-4-yl)-4-difluoromethoxy-3-cyclopropylmethoxybenzamide, (−)p-[(4aR*,10bS*)-9-ethoxy-1,2,3,4,4a,10b-hexahydro-8-methoxy-2-methylbenzo[s][1,6]naphthyridin-6-yl]-N,N-diisopropylbenzamide, (R)-(+)-1-(4-bromobenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidone, 3-(cyclopentyloxy-4-methoxyphenyl)-1-(4-N′-[N-2-cyano-S-methyl-isothioureido]benzyl)-2-pyrrolidone, cis[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylic acid], 2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexane-1-one, cis[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol], (R)-(+)-ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-ylidene]acetate, (S)-(−)-ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-ylidene]acetate, 9-cyclopentyl-5,6-dihydro-7-ethyl-3-(2-thienyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine and 9-cyclopentyl-5,6-dihydro-7-ethyl-3-(tert-butyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine, optionally in the form of the racemates, enantiomers or diastereomers and optionally in the form of the pharmacologically acceptable acid addition salts, solvates and/or hydrates thereof.

Particularly preferably the PDE4-inhibitor is selected from among enprofyllin, roflumilast, ariflo (cilomilast), arofyllin, atizoram, AWD-12-281 (GW-842470), T-440, T-2585, PD-168787, V-11294A, C1-1018, CDC-801, D-22888, YM-58997, Z-15370, N-(3,5-dichloro-1-oxo-pyridin-4-yl)-4-difluoromethoxy-3-cyclopropylmethoxybenzamide, cis[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylic acid], 2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-one, cis[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol], 9-cyclopentyl-5,6-dihydro-7-ethyl-3-(2-thienyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine and 9-cyclopentyl-5,6-dihydro-7-ethyl-3-(tert-butyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine, optionally in the form of the racemates, enantiomers or diastereomers and optionally in the form of the pharmacologically acceptable acid addition salts, solvates and/or hydrates thereof.

By acid addition salts with pharmacologically acceptable acids which the above-mentioned PDE4-inhibitors might be in a position to form are meant, for example, salts selected from among the hydrochloride, hydrobromide, hydroiodide, hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate, hydrobenzoate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate, preferably hydrochloride, hydrobromide, hydrosulphate, hydrophosphate, hydrofumarate and hydromethanesulphonate.

LTD4-antagonists which may be used are preferably compounds selected from among montelukast, pranlukast, zafirlukast, MCC-847 (ZD-3523), MN-001, MEN-91507 (LM-1507), VUF-5078, VUF-K-8707, L-733321, 1-(((R)-(3-(2-(6,7-difluoro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy-2-propyl)phenyl)thio)methylcyclopropane-acetic acid, 1-(((1(R)-3(3-(2-(2,3-dichlorothieno[3,2-b]pyridin-5-yl)-(E)-ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropane-acetic acid and [2-[[2-(4-tert-butyl-2-thiazolyl)-5-benzofuranyl]oxymethyl]phenyl]acetic acid, optionally in the form of the racemates, enantiomers or diastereomers, optionally in the form of the pharmacologically acceptable acid addition salts and optionally in the form of the salts and derivatives, solvates and/or hydrates thereof.

Preferably the LTD4-antagonist is selected from among montelukast, pranlukast, zafirlukast, MCC-847 (ZD-3523), MN-001, MEN-91507 (LM-1507), VUF-5078, VUF-K-8707 and L-733321, optionally in the form of the racemates, enantiomers or diastereomers, optionally in the form of the pharmacologically acceptable acid addition salts and optionally in the form of the salts and derivatives, solvates and/or hydrates thereof.

Particularly preferably the LTD4-antagonist is selected from among montelukast, pranlukast, zafirlukast, MCC-847 (ZD-3523), MN-001 and MEN-91507 (LM-1507), optionally in the form of the racemates, enantiomers or diastereomers, optionally in the form of the pharmacologically acceptable acid addition salts and optionally in the form of the salts and derivatives, solvates and/or hydrates thereof.

By acid addition salts with pharmacologically acceptable acids which the LTD4-antagonists may be capable of forming are meant, for example, salts selected from among the hydrochloride, hydrobromide, hydroiodide, hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate, hydrobenzoate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate, preferably hydrochloride, hydrobromide, hydrosulphate, hydrophosphate, hydrofumarate and hydromethanesulphonate. By salts or derivatives which the LTD4-antagonists may be capable of forming are meant, for example: alkali metal salts, such as, for example, sodium or potassium salts, alkaline earth metal salts, sulphobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogen phosphates, palmitates, pivalates or furoates.

The EGFR-inhibitors used are preferably compounds selected from among 44(3-chloro-4-fluorophenyl)aminol-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-diethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline, 4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[44(R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[44(R)-2-methoxymethyl-6-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[24(S)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline, 4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(N,N-bis-(2-methoxy-ethyl)-amino)-1-oxo-2-buten-1-yl]amino}-cyclopropylmethoxy-quinazoline, 4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-ethyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline, 4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline, 4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(tetrahydropyran-4-yl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((R)-tetrahydrofuran-3-yloxy)-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopentyloxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N-cyclopropyl-N-methyl-amino)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N, N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6,7-bis-(2-methoxy-ethoxy)-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(morpholin-4-yl)-propyloxy]-6-[(vinylcarbonyl)amino]-quinazoline, 4-[(R)-(1-phenyl-ethyl)amino]-6-(4-hydroxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin, 3-cyano-4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N, N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-ethoxy-quinoline, 4-{[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]amino}-6-(5-{[(2-methanesulphonyl-ethyl)amino]methyl}-furan-2-yl)quinazoline, 4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N,N-bis-(2-methoxy-ethyl)-amino]-1-oxo-2-buten-1-yl}amino)-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-{[4-(5,5-dimethyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-7-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-6-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{2-[4-(2-oxo-morpholin-4-yl)-piperidin-1-yl]-ethoxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-amino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methanesulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(methoxymethyl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-3-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-acetylamino-ethyl)-piperidin-4-yloxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-ethoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-64(S)-tetrahydrofuran-3-yloxy)-7-hydroxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(dimethylamino)sulphonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)sulphonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-acetylamino-ethoxy)-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methanesulphonylamino-ethoxy)-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(piperidin-1-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-aminocarbonylmethyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(tetrahydropyran-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)sulphonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-ethanesulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-ethoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-(2-methoxy-ethoxy)-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-acetylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-[1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-(tetrahydropyran-4-yloxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(piperidin-1-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(4-methyl-piperazin-1-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[2-(2-oxopyrrolidin-1-yl)ethyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-(2-methoxy-ethoxy)-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-(1-acetyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7(2-methoxy-ethoxy)-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-isopropyloxycarbonyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-methylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[N-(2-methoxy-acetyl)-N-methyl-amino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-methoxy-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(cis-2,6-dimethyl-morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methyl-morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(S,S)-(2-oxa-5-aza-bicyclo[2,2,1]hept-5-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(N-methyl-N-2-methoxyethyl-amino)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-ethyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methoxyethyl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(3-methoxypropyl-amino)-carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-acetyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[trans-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-dimethylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-cyano-piperidin-4-yloxy)-7-methoxy-quinazoline, Cetuximab, Trastuzumab, ABX-EGF and Mab ICR-62, optionally in the form of the racemates, enantiomers or diastereomers thereof, optionally in the form of the pharmacologically acceptable acid addition salts, the solvates and/or hydrates thereof.

Preferred EGFR inhibitors are selected from among 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-diethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline, 4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[44(R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-2-methoxymethyl-6-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[24(S)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline, 4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(N,N-bis-(2-methoxy-ethyl)-amino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline, 4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-ethyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline, 4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline, 4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(tetrahydropyran-4-yl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((R)-tetrahydrofuran-3-yloxy)-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopentyloxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N-cyclopropyl-N-methyl-amino)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6,7-bis-(2-methoxy-ethoxy)-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(morpholin-4-yl)-propyloxy]-6-[(vinylcarbonyl)amino]-quinazoline, 4-[(R)-(1-phenyl-ethyl)amino]-6-(4-hydroxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidine, 3-cyano-4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-ethoxy-quinoline, 4-{[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]amino}-6-(5-{[(2-methanesulphonyl-ethyl)amino]methyl}-furan-2-yl)quinazoline, 4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N,N-bis-(2-methoxy-ethyl)-amino]-1-oxo-2-buten-1-yl}amino)-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-{[4-(5,5-dimethyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-7-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-6-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{2-[4-(2-oxo-morpholin-4-yl)-piperidin-1-yl]-ethoxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-amino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methanesulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(methoxymethyl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-3-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-acetylamino-ethyl)-piperidin-4-yloxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-ethoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-hydroxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(dimethylamino)sulphonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)sulphonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-acetylamino-ethoxy)-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methanesulphonylamino-ethoxy)-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(piperidin-1-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-aminocarbonylmethyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(tetrahydropyran-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)sulphonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-ethanesulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-ethoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-(2-methoxy-ethoxy)-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-acetylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-[1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-(tetrahydropyran-4-yloxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(piperidin-1-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(4-methyl-piperazin-1-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[2-(2-oxopyrrolidin-1-yl)ethyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-(2-methoxy-ethoxy)-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-(1-acetyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7(2-methoxy-ethoxy)-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-isopropyloxycarbonyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-methylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[N-(2-methoxy-acetyl)-N-methyl-amino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-methoxy-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(cis-2,6-dimethyl-morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methyl-morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(S,S)-(2-oxa-5-aza-bicyclo[2,2,1]hept-5-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(N-methyl-N-2-methoxyethyl-amino)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-ethyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methoxyethyl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(3-methoxypropyl-amino)-carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-acetyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[trans-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-dimethylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-cyano-piperidin-4-yloxy)-7-methoxy-quinazoline, and Cetuximab, optionally in the form of the racemates, enantiomers or diastereomers thereof, optionally in the form of the pharmacologically acceptable acid addition salts, the solvates and/or hydrates thereof.

It is particularly preferable within the scope of the present invention to use those EGFR-inhibitors which are selected from among 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline, 4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[44(R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[24(S)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline, 4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(tetrahydropyran-4-yl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopentyloxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6,7-bis-(2-methoxy-ethoxy)-quinazoline, 4-[(R)-(1-phenyl-ethyl)amino]-6-(4-hydroxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidine, 3-cyano-4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-ethoxy-quinoline, 4-[(R)-(1-phenyl-ethyl)amino]-6-{[44(R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-{[4-(5,5-dimethyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{2-[4-(2-oxo-morpholin-4-yl)-piperidin-1-yl]-ethoxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-amino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methanesulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-3-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-acetylamino-ethyl)-piperidin-4-yloxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-ethoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(piperidin-1-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-ethanesulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-(2-methoxy-ethoxy)-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-(tetrahydropyran-4-yloxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(piperidin-1-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[2-(2-oxopyrrolidin-1-yl)ethyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-(1-acetyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7(2-methoxy-ethoxy)-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(N-methyl-N-2-methoxyethyl-amino)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-ethyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-acetyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[trans-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-dimethylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-cyano-piperidin-4-yloxy)-7-methoxy-quinazoline, and 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methoxyethyl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, optionally in the form of the racemates, enantiomers or diastereomers thereof, optionally in the form of the pharmacologically acceptable acid addition salts, the solvates and/or hydrates thereof.

Particularly preferred EGFR-inhibitors according to the invention are the compounds selected from among 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6,7-bis-(2-methoxy-ethoxy)-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-{[4-(5,5-dimethyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methanesulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[2-(2-oxopyrrolidin-1-yl)ethyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-(1-acetyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methoxyethyl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-acetyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[trans-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-dimethylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline and 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-cyano-piperidin-4-yloxy)-7-methoxy-quinazoline optionally in the form of the racemates, enantiomers or diastereomers thereof, optionally in the form of the pharmacologically acceptable acid addition salts, the solvates and/or hydrates thereof.

By acid addition salts with pharmacologically acceptable acids which the EGFR-inhibitors may be capable of forming are meant, for example, salts selected from among the hydrochloride, hydrobromide, hydroiodide, hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate, hydrobenzoate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate, preferably hydrochloride, hydrobromide, hydrosulphate, hydrophosphate, hydrofumarate and hydromethanesulphonate.

Examples of dopamine agonists which may be used preferably include compounds selected from among bromocriptine, cabergoline, alpha-dihydroergocryptine, lisuride, pergolide, pramipexol, roxindol, ropinirol, talipexol, terguride and viozan. Any reference to the above-mentioned dopamine agonists within the scope of the present invention includes a reference to any pharmacologically acceptable acid addition salts and optionally hydrates thereof which may exist. By the physiologically acceptable acid addition salts which may be formed by the above-mentioned dopamine agonists are meant, for example, pharmaceutically acceptable salts which are selected from the salts of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid and maleic acid.

Examples of H1-antihistamines preferably include compounds selected from among epinastine, cetirizine, azelastine, fexofenadine, levocabastine, loratadine, mizolastine, ketotifen, emedastine, dimetinden, clemastine, bamipin, cexchlorpheniramine, pheniramine, doxylamine, chlorophenoxamine, dimenhydrinate, diphenhydramine, promethazine, ebastine, desloratidine and meclozine. Any reference to the above-mentioned H1-antihistamines within the scope of the present invention includes a reference to any pharmacologically acceptable acid addition salts which may exist.

Examples of PAF-antagonists preferably include compounds selected from among 4-(2-chlorophenyl)-9-methyl-2-[3(4-morpholinyl)-3-propanon-1-yl]-6H-thieno-[3,24]-[1,2,4]triazolo[4,3-a][1,4]diazepines, 6-(2-chlorophenyl)-8,9-dihydro-1-methyl-8-[(4-morpholinyl)carbonyl]-4H,7H-cyclo-penta-[4,5]thieno-[3,24][1,2,4]triazolo[4,3-a][1,4]diazepines.

MRP4-inhibitors used are preferably compounds selected from among N-acetyl-dinitrophenyl-cysteine, cGMP, cholate, diclofenac, dehydroepiandrosterone 3-glucuronide, dehydroepiandrosterone 3-sulphate, dilazep, dinitrophenyl-s-glutathione, estradiol 17-β-glucuronide, estradiol 3,17-disulphate, estradiol 3-glucuronide, estradiol 3-sulphate, estrone 3-sulphate, flurbiprofen, folate, N5-formyl-tetrahydrofolate, glycocholate, clycolithocholic acid sulphate, ibuprofen, indomethacin, indoprofen, ketoprofen, lithocholic acid sulphate, methotrexate, MK571 ((E)-3-[[[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-[[3-dimethylamino)-3-oxopropyl]thio]methyl]thio]-propanoic acid), α-naphthyl-β-D-glucuronide, nitrobenzyl mercaptopurine riboside, probenecid, PSC833, sildenafil, sulfinpyrazone, taurochenodeoxycholate, taurocholate, taurodeoxycholate, taurolithocholate, taurolithocholic acid sulphate, topotecan,

trequinsin and zaprinast, dipyridamole, optionally in the form of the racemates, enantiomers, diastereomers and the pharmacologically acceptable acid addition salts and hydrates thereof.

Preferably the invention relates to the use of MRP4-inhibitors for preparing a pharmaceutical composition for the treatment of respiratory complaints, containing the PDE4B-inhibitors and MRP4-inhibitors, the MRP4-inhibitors preferably being selected from among N-acetyl-dinitrophenyl-cysteine, dehydroepiandrosterone 3-sulphate, dilazep, dinitrophenyl-S-glutathione, estradiol 3,17-disulphate, flurbiprofen, glycocholate, glycolithocholic acid sulphate, ibuprofen, indomethacin, indoprofen, lithocholic acid sulphate, MK571, PSC833, sildenafil, taurochenodeoxycholate, taurocholate, taurolithocholate, taurolithocholic acid sulphate, trequinsin and zaprinast, dipyridamole, optionally in the form of the racemates, enantiomers, diastereomers and the pharmacologically acceptable acid addition salts and hydrates thereof.

The invention relates more preferably to the use of MRP4-inhibitors for preparing a pharmaceutical composition for treating respiratory complaints, containing the PDE4B-inhibitors and MRP4-inhibitors according to the invention, the MRP4-inhibitors preferably being selected from among dehydroepiandrosterone 3-sulphate, estradiol 3,17-disulphate, flurbiprofen, indomethacin, indoprofen, MK571, taurocholate, optionally in the form of the racemates, enantiomers, diastereomers and the pharmacologically acceptable acid addition salts and hydrates thereof. The separation of enantiomers from the racemates can be carried out using methods known from the art (e.g. chromatography on chiral phases, etc.).

By acid addition salts with pharmacologically acceptable acids are meant, for example, salts selected from among the hydrochlorides, hydrobromides, hydroiodides, hydrosulphates, hydrophosphates, hydromethanesulphonates, hydronitrates, hydromaleates, hydroacetates, hydrobenzoates, hydrocitrates, hydrofumarates, hydrotartrates, hydrooxalates, hydrosuccinates, hydrobenzoates and hydro-p-toluenesulphonates, preferably the hydrochlorides, hydrobromides, hydrosulphates, hydrophosphates, hydrofumarates and hydromethanesulphonates.

The invention further relates to pharmaceutical preparations which contain a triple combination of the PDE4B-inhibitors, MRP4-inhibitors and another active substance according to the invention, such as, for example, an anticholinergic, a steroid, an LTD4-antagonist or a betamimetic, and the preparation thereof and the use thereof for treating respiratory complaints.

The iNOS-inhibitors used are preferably compounds selected from among: S-(2-aminoethyl)isothiourea, aminoguanidine, 2-aminomethylpyridine, AMT, L-canavanine, 2-iminopiperidine, S-isopropylisothiourea, S-methylisothiourea, S-ethylisothiourea, S-methyltiocitrulline, S-ethylthiocitrulline, L-NA (N^(ω)-nitro-L-arginine), L-NAME (N^(ω)-nitro-L-arginine methylester), L-NMMA (N^(G)-monomethyl-L-arginine), L-NIO (N^(ω)-iminoethyl-L-ornithine), L-NIL (N^(ω)-iminoethyl-lysine), (S)-6-acetimidoylamino-2-amino-hexanoic acid (1H-tetrazol-5-yl)-amide (SC-51) (J. Med. Chem. 2002, 45, 1686-1689), 1400W, (S)-4-(2-acetimidoylamino-ethylsulphanyl)-2-amino-butyric acid (GW274150) (Bioorg. Med. Chem. Lett. 2000, 10, 597-600), 2-[2-(4-methoxy-pyridin-2-yl)-ethyl]-3H-imidazo[4,5-b]pyridine (BYK191023) (Mol. Pharmacol. 2006, 69, 328-337), 2-((R)-3-amino-1-phenyl-propoxy)-4-chloro-5-fluorobenzonitrile (WO 01/62704), 2-((1R.3S)-3-amino-4-hydroxy-1-thiazol-5-yl-butylsulphanyl)-6-trifluoromethyl-nicotinonitrile (WO 2004/041794), 2-((1R.3S)-3-amino-4-hydroxy-1-thiazol-5-yl-butylsulphanyl)-4-chloro-benzonitrile (WO 2004/041794), 2-((1R.3S)-3-amino-4-hydroxy-1-thiazol-5-yl-butylsulphanyl)-5-chloro-benzonitrile (WO 2004/041794), (2S,4R)-2-amino-4-(2-chloro-5-trifluoromethyl-phenylsulphanyl)-4-thiazol-5-yl-butan-1-ol (WO 2004/041794), 2-((1R.3S)-3-amino-4-hydroxy-1-thiazol-5-yl-butylsulphanyl)-5-chloro-nicotinonitrile (WO 2004/041794), 4-((S)-3-amino-4-hydroxy-1-phenyl-butylsulphanyl)-6-methoxy-nicotinonitrile (WO 02/090332), substituted 3-phenyl-3,4-dihydro-1-isoquinolinamines such as e.g. AR-C102222 (J. Med. Chem. 2003, 46, 913-916), (1S.5S.6R)-7-chloro-5-methyl-2-aza-bicyclo[4.1.0]hept-2-en-3-ylamine (ONO-1714) (Biochem. Biophys. Res. Commun. 2000, 270, 663-667), (4R.5R)-5-ethyl-4-methyl-thiazolidin-2-ylideneamine (Bioorg. Med. Chem. 2004, 12, 4101), (4R.5R)-5-ethyl-4-methyl-selenazolidin-2-ylideneamine (Bioorg. Med. Chem. Lett. 2005, 15, 1361), 4-aminotetrahydrobiopterine (Curr. Drug Metabol. 2002, 3, 119-121), (E)-3-(4-chloro-phenyl)-N-(1-{2-oxo-2-[4-(6-trifluoromethyl-pyrimidin-4-yloxy)-piperidin-1-yl]-ethylcarbamoyl}-2-pyridin-2-yl-ethyl)-acrylamide (FR260330) (Eur. J. Pharmacol. 2005, 509, 71-76), 3-(2,4-difluoro-phenyl)-6-[2-(4-imidazol-1-ylmethyl-phenoxy)-ethoxy]-2-phenyl-pyridine (PPA250) (J. Pharmacol. Exp. Ther. 2002, 303, 52-57), methyl 3-{[(benzo[1.3]dioxol-5-ylmethyl)-carbamoyl]-methyl}-4-(2-imidazol-1-yl-pyrimidin-4-yl)-piperazin-1-carboxylate (BBS-1) (Drugs Future 2004, 29, 45-52), (R)-1-(2-imidazol-1-yl-6-methyl-pyrimidin-4-yl)-pyrrolidine-2-carboxylic acid (2-benzo[1.3]dioxol-5-yl-ethyl)-amide (BBS-2) (Drugs Future 2004, 29, 45-52) and the pharmaceutical salts, prodrugs or solvates thereof.

Other iNOS-inhibitors which may be used within the scope of the present invention are antisense oligonucleotides, particularly antisense oligonucleotides that bind iNOS-coding nucleic acids. For example, WO 01/52902 describes antisense oligonucleotides, particularly antisense-oligonucleotides, which bind iNOS-coding nucleic acids, for modulating the expression of iNOS. Those iNOS-antisense-oligonucleotides as described particularly in WO 01/52902 may therefore also be combined with the PDE4-inhibitors of the present invention on the basis of their similar activity to the iNOS inhibitors.

Compounds which may be used as SYK-inhibitors are preferably compounds selected from among: R343 or R788.

Pharmaceutical Formulations

Suitable forms for administration are for example tablets, capsules, solutions, syrups, emulsions or inhalable powders or aerosols. The content of the pharmaceutically effective compound(s) in each case should be in the range from 0.1 to 90 wt. %, preferably 0.5 to 50 wt. % of the total composition, i.e. in amounts which are sufficient to achieve the dosage range specified hereinafter.

The preparations may be administered orally in the form of a tablet, as a powder, as a powder in a capsule (e.g. a hard gelatine capsule), as a solution or suspension. When administered by inhalation the active substance combination may be given as a powder, as an aqueous or aqueous-ethanolic solution or using a propellant gas formulation.

Preferably, therefore, pharmaceutical formulations are characterised in that they contain one or more compounds of formula I according to the preferred embodiments above.

It is particularly preferable if the compounds of formula I are administered orally, and it is also particularly preferable if they are administered once or twice a day. Suitable tablets may be obtained, for example, by mixing the active substance(s) with known excipients, for example inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatine, lubricants such as magnesium stearate or talc and/or agents for delaying release, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate. The tablets may also comprise several layers.

Coated tablets may be prepared accordingly by coating cores produced analogously to the tablets with substances normally used for tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar. To achieve delayed release or prevent incompatibilities the core may also consist of a number of layers. Similarly the tablet coating may consist of a number of layers to achieve delayed release, possibly using the excipients mentioned above for the tablets.

Syrups containing the active substances or combinations thereof according to the invention may additionally contain a sweetener such as saccharine, cyclamate, glycerol or sugar and a flavour enhancer, e.g. a flavouring such as vanillin or orange extract. They may also contain suspension adjuvants or thickeners such as sodium carboxymethyl cellulose, wetting agents such as, for example, condensation products of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoates.

Capsules containing one or more active substances or combinations of active substances may for example be prepared by mixing the active substances with inert carriers such as lactose or sorbitol and packing them into gelatine capsules.

Suitable suppositories may be made for example by mixing with carriers provided for this purpose, such as neutral fats or polyethyleneglycol or the derivatives thereof.

Excipients which may be used include, for example, water, pharmaceutically acceptable organic solvents such as paraffins (e.g. petroleum fractions), vegetable oils (e.g. groundnut or sesame oil), mono- or polyfunctional alcohols (e.g. ethanol or glycerol), carriers such as e.g. natural mineral powders (e.g. kaolins, clays, talc, chalk), synthetic mineral powders (e.g. highly dispersed silicic acid and silicates), sugars (e.g. cane sugar, lactose and glucose), emulsifiers (e.g. lignin, spent sulphite liquors, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc, stearic acid and sodium lauryl sulphate).

For oral administration the tablets may, of course, contain, apart from the abovementioned carriers, additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various additives such as starch, preferably potato starch, gelatine and the like. Moreover, lubricants such as magnesium stearate, sodium lauryl sulphate and talc may be used at the same time for the tabletting process. In the case of aqueous suspensions the active substances may be combined with various flavour enhancers or colourings in addition to the excipients mentioned above.

It is also preferred if the compounds of formula I are administered by inhalation, particularly preferably if they are administered once or twice a day. For this purpose, the compounds of formula I have to be made available in forms suitable for inhalation. Inhalable preparations include inhalable powders, propellant-containing metered-dose aerosols or propellant-free inhalable solutions, which are optionally present in admixture with conventional physiologically acceptable excipients.

Within the scope of the present invention, the term propellant-free inhalable solutions also includes concentrates or sterile ready-to-use inhalable solutions. The preparations which may be used according to the invention are described in more detail in the next part of the specification.

Inhalable Powders

If the active substances of formula I are present in admixture with physiologically acceptable excipients, the following physiologically acceptable excipients may be used to prepare the inhalable powders according to the invention: monosaccharides (e.g. glucose or arabinose), disaccharides (e.g. lactose, saccharose, maltose), oligo- and polysaccharides (e.g. dextran), polyalcohols (e.g. sorbitol, mannitol, xylitol), salts (e.g. sodium chloride, calcium carbonate) or mixtures of these excipients with one another. Preferably, mono- or disaccharides are used, while the use of lactose or glucose is preferred, particularly, but not exclusively, in the form of their hydrates. For the purposes of the invention, lactose is the particularly preferred excipient, while lactose monohydrate is most particularly preferred. Methods of preparing the inhalable powders according to the invention by grinding and micronising and by finally mixing the components together are known from the prior art.

Propellant-Containing Inhalable Aerosols

The propellant-containing inhalable aerosols which may be used according to the invention may contain 1 dissolved in the propellant gas or in dispersed form. The propellant gases which may be used to prepare the inhalation aerosols according to the invention are known from the prior art. Suitable propellant gases are selected from among hydrocarbons such as n-propane, n-butane or isobutane and halohydrocarbons such as preferably fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane. The propellant gases mentioned above may be used on their own or in mixtures thereof. Particularly preferred propellant gases are fluorinated alkane derivatives selected from TG134a (1,1,1,2-tetrafluoroethane), TG227 (1,1,1,2,3,3,3-heptafluoropropane) and mixtures thereof. The propellant-driven inhalation aerosols used within the scope of the use according to the invention may also contain other ingredients such as co-solvents, stabilisers, surfactants, antioxidants, lubricants and pH adjusters. All these ingredients are known in the art.

Propellant-Free Inhalable Solutions

The compounds of formula I according to the invention are preferably used to prepare propellant-free inhalable solutions and inhalable suspensions. Solvents used for this purpose include aqueous or alcoholic, preferably ethanolic solutions. The solvent may be water on its own or a mixture of water and ethanol. The solutions or suspensions are adjusted to a pH of 2 to 7, preferably 2 to 5, using suitable acids. The pH may be adjusted using acids selected from inorganic or organic acids. Examples of particularly suitable inorganic acids include hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid and/or phosphoric acid. Examples of particularly suitable organic acids include ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and/or propionic acid etc. Preferred inorganic acids are hydrochloric and sulphuric acids. It is also possible to use the acids which have already formed an acid addition salt with one of the active substances. Of the organic acids, ascorbic acid, fumaric acid and citric acid are preferred. If desired, mixtures of the above acids may also be used, particularly in the case of acids which have other properties in addition to their acidifying qualities, e.g. as flavourings, antioxidants or complexing agents, such as citric acid or ascorbic acid, for example. According to the invention, it is particularly preferred to use hydrochloric acid to adjust the pH. Co-solvents and/or other excipients may be added to the propellant-free inhalable solutions used for the purpose according to the invention. Preferred co-solvents are those which contain hydroxyl groups or other polar groups, e.g. alcohols—particularly isopropyl alcohol, glycols—particularly propyleneglycol, polyethyleneglycol, polypropyleneglycol, glycolether, glycerol, polyoxyethylene alcohols and polyoxyethylene fatty acid esters. The terms excipients and additives in this context denote any pharmacologically acceptable substance which is not an active substance but which can be formulated with the active substance or substances in the pharmacologically suitable solvent in order to improve the qualitative properties of the active substance formulation. Preferably, these substances have no pharmacological effect or, in connection with the desired therapy, no appreciable or at least no undesirable pharmacological effect. The excipients and additives include, for example, surfactants such as soya lecithin, oleic acid, sorbitan esters, such as polysorbates, polyvinylpyrrolidone, other stabilisers, complexing agents, antioxidants and/or preservatives which guarantee or prolong the shelf life of the finished pharmaceutical formulation, flavourings, vitamins and/or other additives known in the art. The additives also include pharmacologically acceptable salts such as sodium chloride as isotonic agents. The preferred excipients include antioxidants such as ascorbic acid, for example, provided that it has not already been used to adjust the pH, vitamin A, vitamin E, tocopherols and similar vitamins or provitamins occurring in the human body. Preservatives may be used to protect the formulation from contamination with pathogens. Suitable preservatives are those which are known in the art, particularly cetyl pyridinium chloride, benzalkonium chloride or benzoic acid or benzoates such as sodium benzoate in the concentration known from the prior art. For the treatment forms described above, ready-to-use packs of a medicament for the treatment of respiratory complaints are provided, containing an enclosed description including for example the words respiratory disease, COPD or asthma, a pteridine and one or more combination partners selected from those described above.

EXPERIMENTAL PROCEDURES AND SYNTHETIC EXAMPLES List of Abbreviations

-   ACN acetonitrile -   APCI atmospheric pressure chemical ionization (in MS) -   Ctrl control -   DAD diode array detector -   DMA N,N-dimethylacetamide′ -   DMF N,N-dimethylformamide -   DMSO dimethyl sulfoxide -   EI electron impact (in MS) -   ESI electrospray ionization (in MS) -   ex example -   GC/MS gas chromatography with mass spectrometric detection -   h hour(s) -   HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium     hexafluoro-phosphate -   HPLC high performance liquid chromatography -   HPLC/MS coupled high performance liquid chromatography-mass     spectrometry -   min minutes -   MS mass spectrometry -   NMR nuclear magnetic resonance -   R_(t) retention time (in HPLC) -   sec secondary -   TBTU O-(1H-benzo-1,2,3-triazol-1-yl)-N,N,N′,N′-tetramethyluronium     tetrafluoroborate -   tert tertiary -   TFA trifluoroacetic acid -   TLC thin-layer chromatography -   UV ultraviolet absorption

Analytical Methods HPLC Methods Methods:

1A

-   -   Column: Sunfire MS-C8, 5 μm, 4.6×100 mm     -   Mobile phase: A=(10 nM aqueous solution of NH₄COOH)+10% ACN;         -   B=ACN+10% (10 nM aqueous solution of NH₄COOH).     -   Flow rate: 1500 μL/min     -   Gradient: A/B (95/5%) for 1 min then to A/B (5/95%) in 10 min         for 2 min

1E

-   -   Column: Symmetry C8, 5 μm, 3×150 mm     -   Mobile phase: A=(10 nM aqueous solution of NH₄COOH)+10% ACN;         -   B=ACN+10% (10 nM aqueous solution of NH₄COOH).     -   Flow rate: 1200 μL/min     -   Gradient: A (100%) for 1.5 min then to B (100%) in 10 min for 3         min

1E (Fusion)

-   -   Column: Synergy Fusion RP80A, 4 μm, 4.6×100 mm     -   Mobile phase: A=(10 nM aqueous solution of NH₄COOH)+10% ACN;         -   B=ACN+10% (10 nM aqueous solution of NH₄COOH).     -   Flow rate: 1200 μL/min     -   Gradient: A (100%) for 1.5 min then to B (100%) in 10 min for 3         min

1E (Hydro)

-   -   Column: Synergy Hydro RP80A, 4 μm, 4.6×100 mm     -   Mobile phase: A=(10 nM aqueous solution of NH₄COOH)+10% ACN;         -   B=ACN+10% (10 nM aqueous solution of NH₄COOH).     -   Flow rate: 1200 μL/min     -   Gradient: A (100%) for 1.5 min then to B (100%) in 10 min for 3         min

Equipment:

-   -   Instrument: HPLC/MS ThermoFinnigan HPLC Surveyor DAD,     -   Detection: UV @ 254 nm

Detection: Finnigan MSQ, quadrupole

-   -   Ion source: APCI

Method:

1F

-   -   Column: Xterra MS-C8, 3.5 μm, 4.6×50 mm     -   Mobile phase: A=(H₂O+0.1% TFA)+10% ACN; B=ACN     -   Flow rate: 1300 μL/min     -   Gradient: A (100%) then to A/B (10/90%) in 3.25 min for 0.75 min

1Fa

-   -   Column: Xterra MS-C18, 5 μm, 4.6×50 mm     -   Mobile phase: A=(H₂O+0.1% NH4COOH)+10% ACN; B=ACN     -   Flow rate: 1300 μL/min     -   Gradient: A (100%) then to A/B (10/90%) in 3.25 min for 0.75 min

Equipment:

-   -   Instrument: HPLC/MS Waters. Hplc Alliance 2695 DAD, ZQ         Quadrupole     -   Detection: UV @ 254 nm     -   Detection: Waters ZQ, Quadrupole;     -   Ion source: ESI

Methods:

2A

-   -   Column: X-Terra MS C18 4.6×50 mm, 3.5 μm;         -   Column Temperature: 40.0° C.     -   Mobile phase: A=H₂O+0.1% TFA; B=ACN+0.1% TFA     -   Flow rate: 1500 μL/min

Gradient: Time A % B % 0.00 95.00 5.00 2.00 0.00 100.00 2.49 0.00 100.00 2.50 95.00 5.00

2B

-   -   Column: X-Terra MS C18 4.6×50 mm, 3.5 μm;         -   Column Temperature: 40.0° C.     -   Mobile phase: A=H₂O+0.1% TFA; B=ACN+0.1% TFA     -   Flow rate: 1000 μL/min

Gradient: Time A % B % 0.00 95.00 5.00 0.40 95.00 5.00 4.00 2.00 98.00 4.35 2.00 98.00 4.50 95.00 5.00

2C

-   -   Column: Sunfire C18 4.6×50 mm, 3.5 μm;         -   Column Temperature: 40.0° C.     -   Mobile phase: A=H₂O+0.1% TFA; B=ACN+0.1% TFA     -   Flow rate: 1500 μL/min

Gradient: Time: A % B % 0.00 95.00 5.00 2.00 0.00 100.00 2.49 0.00 100.00 2.50 95.00 5.00

Equipment

-   -   Instrument: Waters ZQ2000 mass spectrometer     -   Detection: HP1100 HPLC+DAD (Wavelength range: 210 to 500         nM)+Gilson 215 Autosampler     -   Ion source: ESI+

Method:

2Ca

-   -   Column: MERCK; Chromolith Flash; RP18e; 25×4.6 mm     -   Mobile phase: A=water+0,1% HCOOH; B=ACN+0,1% HCOOH     -   Flow rate: 1.6 ml/min

Gradient: A % B % Time [min] 90 10 0.00 10 90 2.70 10 90 3.00 90 10 3.30

2Cb

-   -   Column: MERCK; Chromolith Flash; RP18e; 25×4.6 mm     -   Mobile: A=water+0,1% HCOOH; B=MeOH     -   Flow rate: 1.6 ml/min

Gradient: A % B % Time [min] 90 10 0.00 0 100 2.50 0 100 3.50

Equipment

-   -   Instrument: Agilent Technology; HP 1200 Series, DAD SL     -   Detection: UV 240-254 nm     -   Detection: Waters ZQ Single Quad     -   Ion source: ESI+

Method:

2F

-   -   Column: Symmetry Shield RP8, 5 μm, 4.6×150 mm     -   Mobile phase: A=(H₂O+HCOOH 0.1%)+10% ACN         -   B=ACN+10% (H₂O+0.1% HCOOH)     -   Flow rate: 1000 μL/min     -   Gradient: A/B (95/5%) for 1.5 min then to A/B (5/95%) in 10 min         for 1.5 min

2M

-   -   Column: Symmetry Shield RP8, 5 μm, 4.6×150 mm     -   Mobile phase: A=(H₂O+HCOOH 0.1%)+10% ACN         -   B=ACN+10% (H₂O+0.1% HCOOH)     -   Flow rate: 1200 μL/min     -   Gradient: A/B (90/10%) for 1.5 min then to A/B (5/95%) in 10 min         for 2 min

Equipment:

-   -   Instrument: HPLC/MS ThermoFinnigan HPLC Surveyor DAD, LCQDuo Ion         Trap     -   Detection: UV λ54 nm     -   Detection: Finnigan LCQDuo Ion Trap     -   Ion source: ESI

Method:

2G

-   -   Eluent: A=H2O+0.05% TFA; B=ACN     -   Column: Waters SunFire C18 30×100 mm 5 μm

Gradient: slope 5%/min Initial: Flow = 40 mL/min % A = 80 % B = 20 8 min Flow = 40 mL/min % A = 40 % B = 60 9 min Flow = 40 mL/min % A = 40 % B = 60 10 min Flow = 40 mL/min % A = 5 % B = 95 11 min Flow = 40 mL/min % A = 5 % B = 95 11.5 min Flow = 40 mL/min % A = 80 % B = 20 Stop run after 12 min Pre-run method: Initial condition for 3 min

Equipment:

Detector MS Waters ZQ: Detector DAD Waters 996: File: APrep_ESI.ipr Start Wavelength: 210 nm Polarity: ESI+ End Wavelength: 600 nm Mass range: 130 to 900 amu Resolution: 1.2 nm Sampling rate: 1 spectra/sec Sample Manager mod Waters 2767: Make up pump mod Waters 515: Injection type: partial loop Flow = 1000 μL/min Injection Volume: set to Open Solvent = ACN/Water/Formic acid Access Login mask (90/10/0.1) Syringe size: 5000 uL Splitter: 1:1000 Trigger: mixed Total scan UV plus MS A Loop Volume: 5000 uL

Method:

2Ga

-   -   Column: BEH C18, 1.8 um, 2.1×100 mm     -   Mobile phase: A=(H₂O+NH4COOH 0.1%)         -   B=ACN+10% H₂O     -   Flow rate: 450 μL/min     -   Gradient: 100% A for 1.5 min then to 100% B in 2.2 min

2Gb

-   -   Column: BEH C18, 1.7 um, 2.1×50 mm     -   Mobile phase: A=H₂O 90%+0.1% TFA+10% ACN         -   B=ACN+10% H₂O     -   Flow rate: 480 μL/min     -   Gradient: A/B (90:10), then to A/B (10:90) in 1.2 minutes for         0.46 minute

Equipment:

-   -   Instrument: UPLC/MS AcquityWaters     -   Detection: UV λ254 nm     -   Detection: Waters SQD, Quadrupole     -   Ion source: ESI

Method:

2H (Isocratic)

-   -   Column: DAICEL (IC) 5 μm, 4.6×250 mm     -   Mobile phase: A=(hexane+0,2% diethylamine); B=(MeOH/EtOH         50/50%).         -   A/B=50/50%     -   Flow rate: 1 ml/min

2I (Isocratic)

-   -   Column: DAICEL AS-H 5 μm, 4.6×250 mm     -   Mobile phase: A=Hexane; B=EtOH (con AS-H), IPA (con AD-H)         -   A/B=98/2%     -   Flow rate: 1 ml/min

Equipment

-   -   Instrument: LC Agilent Technologies. HPLC 1100 Serie, DAD         Version A.     -   Detection: UV 220-300 nm

GC-MS Methods: Method:

3A

-   -   Column: Agilent DB-5MS, 25 m×0.25 mm×0.25 μm     -   Carrier gas: Helium, 1 ml/min costant flow     -   Oven Program: 50° C. (hold 1 min), to 100° C. in 10° C./min, to         200° C. in 20° C./min, to 300° C. in 30° C./min

Equipment

-   -   Instrument: GC/MS Finnigan TRACE GC, TRACE MS quadrupole     -   Detection: TRACE MS quadrupole     -   Ion source: EI

Microwave Heating:

-   -   Discover® CEM instruments, equipped with 10 and 35 mL vessels.

Synthesis of Intermediates

Potassium hydroxide (37.9 g, 0.67 mol) was suspended in 200 ml of dry ethanol, formamidine acetate (28.1 g, 0.27 mol) and diethyl oxalpropionate (50 ml, 0.27 mol) were added and the reaction mixture was stirred under reflux overnight. The reaction mixture was cooled to room temperature and the precipitate formed was filtered, washed with ethanol and diethyl ether, dissolved in 200 ml of water and the solution obtained acidified by a 37% aqueous solution of hydrochloric acid until pH=2. The acidic aqueous solution was concentrated under vacuum and the residue obtained was suspended and stirred in 100 ml of methanol. The insoluble inorganic salts were filtered off. The solution was concentrated. 15 g (97.4 mmol) of the desired compound were obtained.

was synthesized in analogy to Intermediate 1a, starting from acetamidine hydrochloride.

Potassium-tert-butylate (185.4 g, 1.65 mol) was dissolved in 650 ml of dry ethanol and added slowly at −10° C. to a suspension of 2-ethyl-3-oxo-succinic-acid diethyl ester (274.3 g, 1.27 mol) and formamidine acetate (171.4 g, 1.65 mol). The reaction mixture was stirred at room temperature overnight, concentrated in vacuum and ice water was added. The mixture was acidified by a 37% aqueous solution of hydrochloric acid until pH=5 and extracted with chloroform. After drying the organic layer, evaporation of the solvent in vacuum and crystallization from ethyl acetate/hexane (2:3) gave 38 g (0.19 mol) of the desired compound.

A suspension of sodium tert-butoxide (3.9 g, 40.5 mmol) in 25 ml dry ethanol was added to a solution of diethyl oxalpropionate (3.0 ml, 16.2 mmol) and O-methylisourea hydrochloride (2.15 g, 19.5 mmol) in 25 ml dry ethanol and the reaction mixture was refluxed for 18 h. The reaction mixture was allowed to cool to room temperature and the precipitate removed by filtration. The filtrate was concentrated in vacuum, and the residue was purified by reversed phase HPLC to give the desired product (752 mg, 3.5 mmol).

Intermediate 1d (550 mg, 2.6 mmol) was dissolved in a 4 M aqueous solution of sodium hydroxide (3.0 ml, 12.0 mmol) and stirred for 3 h at room temperature. The reaction mixture was acidified with concentrated hydrochloric acid to yield the desired product as precipitate (443 mg, 2.4 mmol).

Intermediate 1a (7.0 g, 45.4 mmol) was suspended in 35 ml of thionyl chloride (0.45 mol), 0.10 ml of DMF was added and the reaction mixture was refluxed for 1 h. The reaction mixture was concentrated in vacuum. 8.6 g (45 mmol) of the desired product were obtained and used in the next steps without further purification.

was synthesized in analogy to Intermediate 2a, starting from Intermediate 1b.

was synthesized in analogy to Intermediate 2a, starting from Intermediate 1e.

Potassium carbonate (43.34 g, 0.31 mol) was suspended in 350 ml of dry ethanol. A solution of Intermediate 2a (20 g, 0.10 mol) in 10 ml of dichloromethane was added slowly at 0° C. The reaction mixture was allowed to reach room temperature and stirred for 1 h. Potassium carbonate was filtered off and the solvent was removed under vacuum. The crude product was purified by flash chromatography (BIOTAGE SP1; silica gel cartridge: 65i; eluent: dichloromethane/ethyl acetate=95/5%). 5.3 g (26 mmol) of the desired compound were obtained.

was synthesized in analogy to Intermediate 3a, starting from Intermediate 2b.

Intermediate 1c (38 g, 0.19 mol) was added to a mixture of phosphorpentachloride (40.3 g, 0.19 mol) in 240 ml of phosphoroxychloride. The reaction mixture was refluxed until a clear solution was observed. The reaction mixture was concentrated in vacuum. The crude product obtained was purified by distillation in vacuum. 12 g (94.5 mmol) of the desired compound were obtained and used in the next steps without further purification.

5-Bromo-6-hydroxy-pyrimidine-4-carboxylic acid ethyl ester (63 g, 0.26 mol) was suspended in 140 ml of phosphoroxychloride. Phosphorpentachloride (54 g, 0.26 mmol) was added and the reaction mixture was refluxed 72 h. The reaction mixture was concentrated in vacuum and the crude product was suspended and stirred in warmed-up hexane (50° C.); a precipitate was formed and filtered off. The filtrate was concentrated under vacuum to obtain 64 g (243 mmol) of the desired product which was used in the next steps without further purification.

3-Phenylcyclohexanone (500 mg, 2.87 mmol) and 1-isocyanomethanesulfonyl-4-methyl-benzene (750 mg, 3.84 mmol) in 10 ml of 1,2-dimethoxyethane were stirred at 0° C. A solution of potassium tert-butoxide (650 mg, 5.79 mmol) in 10 ml of 1,2-dimethoxyethane and 20 ml of tert-butanol was added dropwise and the reaction mixture was allowed to reach room temperature and stirred overnight. The reaction mixture was diluted with diethyl ether and washed with ice water. The organic phase was separated, washed with brine, dried over sodium sulfate and concentrated under vacuum. 439 mg (2.3 mmol) of the desired product were obtained.

was synthesized in analogy to Intermediate 4a, starting from (R)-3-Phenylcyclohexanone.

GC/MS (method 3A) R_(t)=11.52 min and 11.68 min (diastereoisomeric mixture)

[M]⁺=185

was synthesized in analogy to Intermediate 4a, starting from (S)-3-Phenylcyclohexanone.

GC/MS (method 3A) R_(t)=11.50 min and 11.65 min (diastereoisomeric mixture)

[M]⁺=185

The following intermediates were synthesized in analogy to Intermediates 4a.

Inter- Starting me- ketone diate STRUCTURE 3-(4-Chloro- phenyl)- cyclohexanone 4d

3-(4-Fluoro- phenyl)- cyclohexanone 4e

3-(4-Methoxy- phenyl)- cyclohexanone 4f

3-(4-Methyl- phenyl)- cyclohexanone 4g

3-(3-Fluoro- phenyl)- cyclohexanone 4h

3-isopropyl- cyclohexanone 4i

3-(5-Methyl-furan- 2-yl)-cyclo- hexanone 4j

3-Phenylcyclo- pentanone 4k

3-(4-Chloro- phenyl)- cyclopentanone 4l

3-(4-Fluoro- phenyl)- cyclopentanone 4m

Intermediate 4j (400 mg, 2.11 mmol) was purified by flash chromatography (Biotage SP1 cartridge 25 g; eluent: cyclohexane/ethyl acetate=99/1%). 60 mg (0.22 mmol) of diastereoisomerically pure cis-intermediate was eluted as second fraction (relative stereochemistry assigned by NMR).

GC/MS (method 3A) R_(t)=9.62 min

[M]⁺=189

Intermediate 4n (120 mg, 4.22 mmol) was separated by chiral semipreparative HPLC. 20 mg of enantiomerically pure intermediate 4o were obtained (absolute stereochemistry unknown). Chiral HPLC (method 2I (isocratic)) R_(t)=6.94 min

Further elution of the column gave 20 mg of enantiomerically pure intermediate 4p (absolute stereochemistry unknown).

Chiral HPLC (method 2I (isocratic)) R_(t)=7.27

Intermediate 4b (2.1 g, 11.28 mmol) was stirred under reflux in 20 ml of 96% sulfuric acid and 20 ml of water overnight. The reaction mixture was cooled, treated with a 30% aqueous solution of sodium hydroxide and ice and washed with dichloromethane. The basic water phase was treated with 37% aqueous solution of hydrochloric acid. The acidic aqueous solution was extracted with dichloromethane. The organic phase was washed with brine, dried over sodium sulfate and concentrated under vacuum. 1.85 g (9.1 mmol) of the desired compound were obtained as a diastereoisomeric mixture and used in the next steps without further purification.

Intermediate 5 (1.85 g, 9.06 mmol, mixture of 2 diastereomers) and triethylamine (2.02 ml, 14 mmol) were stirred at 0° C. in 10 ml of tetrahydrofuran. A solution of ethylchloroformate (1.29 ml, 13.58 mmol) in 5 ml of tetrahydrofuran was added dropwise and the reaction mixture was stirred at 0° C. for 1 h. Then, 10 ml of a 30% aqueous solution of ammonium hydroxide were added dropwise and the reaction mixture was allowed to reach room temperature and stirred overnight. The reaction mixture was concentrated under vacuum, dissolved with dichloromethane, washed with a 1M aqueous solution of sodium hydroxide, washed with brine, dried over sodium sulfate and concentrated under vacuum. The crude product was purified by flash chromatography (Isolute silica cartridge 70 g; eluent: dichloromethane/methanol=99/1%). 145 mg (0.71 mmol) of diastereoisomerically pure (1R,3R)-3-phenyl-cyclohexanecarboxylic acid amide (relative stereochemistry assigned by NMR) were obtained.

GC/MS (method 3A) R_(t)=12.88 min

[M]⁺=203

Further elution of the column gave 230 mg (1.13 mmol) of the diastereoisomerically pure (1S,3R)-3-phenyl-cyclohexanecarboxylic acid amide (relative stereochemistry assigned by NMR).

GC/MS (method 3A) R_(t)=13.03 min

[M]⁺=203

Intermediate 4c (300 mg, 1.61 mmol) was stirred under reflux in 2 ml of 96% sulfuric acid and 2 ml of water for 3 h. The reaction mixture was cooled, treated with a 30% aqueous solution of sodium hydroxide and ice and washed with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate and concentrated under vacuum. The crude product was purified by flash chromatography (Isolute silica cartridge 20 g; eluent: dichloromethane/methanol=99/1%). 37 mg (0.18 mmol) of the diastereomerically pure (1S,3S)-3-phenyl-cyclohexanecarboxylic acid amide were obtained (relative stereochemistry assigned by NMR).

GC/MS (method 3A) R_(t)=12.88 min

[M]⁺=203

Further elution of the column gave 40 mg of the diastereomerically pure (1R,3S)-3-phenyl-cyclohexanecarboxylic acid amide (0.2 mmol) (relative stereochemistry assigned by NMR).

GC/MS (method 3A) R_(t)=13.03 min

[M]⁺=203

5-Bromo-3-furan carboxylic acid (1.0 g, 5.23 mmol), phenylboronic acid (0.77 g, 6.28 mmol), tetrakis(triphenylphosphine)palladium(0) (1.21 g, 1.04 mmol) and a 2M solution of sodium carbonate (6.28 ml, 12.57 mmol) were dissolved in 12 ml of 1,2-dimethoxy-ethane and the reaction mixture was stirred under nitrogen atmosphere at 80° C. for 18 h. The reaction mixture was cooled to room temperature, diluted with dichloromethane and treated with a 1M aqueous solution of hydrochloric acid until pH 1. The organic phase was separated, dried over sodium sulphate and concentrated under vacuum. The carboxylic acid was obtained and used without further purification for the synthesis of intermediate 6e in analogy to intermediate 6a.

Intermediate 6f was synthesized in analogy to intermediate 6a, starting from trans 3-(4-chlorophenyl)-cyclobutan carboxylic acid (prepared as described in literature for the preparation of trans 3-phenyl-cyclobutan-carboxylic acid: Wiberg, K. B.; Dailey, W. P.; Walker, F. H.; Waddell, S. T.; Crocker, L. S.; Newton, M. Journal of the American Chemical Society; 1985, 107, 7247-7257).

Intermediate 6g was synthesized in analogy to Intermediate 6a, starting from cis 3-(4-chlorophenyl)-cyclobutan carboxylic acid (prepared as described in literature for the preparation of cis 3-phenyl-cyclobutan-carboxylic acid: Wiberg, K. B.; Dailey, W. P.; Walker, F. H.; Waddell, S. T.; Crocker, L. S.; Newton, M. Journal of the American Chemical Society; 1985, 107, 7247-7257).

Intermediate 4a (390 mg, 2.10 mmol) and Raney-Nickel (10 mg) in 10 ml of 1M solution of ammonia in ethanol was stirred under a hydrogen atmosphere (4 bar) overnight. The reaction mixture was filtered on a celite pad and concentrated under vacuum. The crude product was purified by flash chromatography (dichloromethane/methanol/NH₃(30% aqueous solution)=95/5/0.1%) to obtain 217 mg (1.15 mmol) of the desired product.

2.85 ml of a 1M solution of lithium aluminium hydride (2.85 mmol) in tetrahydrofuran was dissolved in 10 ml of tetrahydrofuran and stirred at 0° C. under nitrogen atmosphere.

Intermediate 6a (145 mg, 0.71 mmol) in 10 ml of tetrahydrofuran was added dropwise. The reaction mixture was stirred at 0° C. for 2 h and then quenched with water and ice. The reaction mixture was extracted with dichloromethane. The organic phase was washed with a 1M aqueous solution of sodium hydroxide, brine, dried over sodium sulfate and concentrated under vacuum. 100 mg (0.55 mmol) of the desired product were obtained.

GC/MS (method 3A) R_(t)=11.53 min

[M]⁺=189

was synthesized in analogy to Intermediate 7b, starting from Intermediate 6b.

GC/MS (method 3A) R_(t)=11.47 min

[M]⁺=189

was synthesized in analogy to Intermediate 7b, starting from Intermediate 6c.

GC/MS (method 3A) R_(t)=11.53 min

[M]⁺=189

was synthesized in analogy to Intermediate 7b, starting from Intermediate 6d.

GC/MS (method 3A) R_(t)=13.03 min

[M]⁺=189

The following intermediates were synthesised in atalogy to Intermediate 7a.

Starting Inter- Inter- mediate mediate STRUCTURE 4d 7f

4e 7g

4f 7h

4g 7i

4h 7j

4i 7k

4k 7l

4l 7m

4m 7n

4n 7o

4o 7p

4p 7q

was synthesized in analogy to intermediate 7b, starting from intermediate 6e.

was synthesized in analogy to intermediate 7b, starting from intermediate 6f.

was obtained and isolated as side product in the preparation of Intermediate 7s

was synthesized in analogy to Intermediate 7b, starting from Intermediate 6g.

was obtained and isolated as side product in the preparation of Intermediate 7u.

Tris(dibenzylideneacetone)dipalladium (1.71 g, 1.87 mmol) and 2,2′-bis(diphenylphosphino)-1,1′-binapthyl (2.32 g, 3.72 mmol) were stirred in 30 ml of toluene for 10 min under argon atmosphere.

Piperidine-3-yl-methyl-carbamic acid tert-butyl ester (2 g, 9.33 mmol), bromobenzene (1.27 ml, 0.01 mol) and sodium tert-butoxide (1.43 g, 14.93 mmol) were added and the reaction mixture was stirred under reflux overnight. The reaction mixture was concentrated under vacuum, the crude product was dissolved in dichloromethane and the organic phase was filtered on a celite pad. The organic phase was washed with an aqueous saturated sodium carbonate solution, with brine, dried over sodium sulfate, concentrated under vacuum. The crude product obtained was dissolved in methanol and loaded onto a SCX cartridge (25 g). After washing with methanol the product was eluted with a 2M solution of ammonia in methanol. 1.17 g (4.03 mmol) of the desired product were obtained and used in next steps without any other purification.

To a solution of Intermediate 8a (1.1 g, 3.79 mmol) in 10 ml of 1,4-dioxane, a 4M solution of hydrochloric acid in 1,4-dioxane (15 ml, 60 mmol) was added dropwise; the reaction mixture was stirred at room temperature overnight before being concentrated under vacuum. The crude product was purified by flash chromatography (Isolute silica gel cartridge: 50 g; eluent: dichloromethane/methanol=95/5%). 250 mg (1.31 mmol) of the desired compound were obtained.

The following intermediates were synthesized in analogy to Intermediates 8a and 9a.

Inter- Starting Starting me- Inter- amine bromide diate STRUCTURE mediate STRUCTURE (S)-1- Pyrrolidin- 3-ylmethyl- carbamic acid tert- butyl ester bromo- benzene 8b

9b

(R)-1- Pyrrolidin- 3-ylmethyl- carbamic acid tert- butyl ester bromo- benzene 8c

9c

Piperidine- 3-yl- methyl- carbamic acid tert- butyl ester 1-bromo- 4-trifluoro methyl- benzene 8d

9d

Piperidine-3-yl-methyl-carbamic acid tert-butyl ester (100 mg, 0.47 mmol), 2-chloro-4-fluoro-benzonitrile (72.5 mg, 0.47 mmol) and N,N-diisopropylethylamine (0.160 ml, 1.23 mmol) were dissolved in 10 ml of DMF and the reaction mixture was stirred at 125° C. overnight. The reaction mixture was concentrated under vacuum and the crude product was purified by flash chromatography (Isolute silica gel cartridge: 5 g; eluent: ethyl acetate). 125 mg (0.36 mmol) of the desired compound were obtained.

To a solution of Intermediate 10 (125 mg, 0.36 mmol) in 5 ml of 1,4-dioxane, a 4M solution of hydrochloric acid in 1,4-dioxane (0.12 ml, 480 mmol) was added dropwise; the reaction mixture was stirred at room temperature overnight before being concentrated under vacuum. 102 mg (0.36 mmol) of the desired compound were obtained.

A solution of 4-methanesulfonylamino-piperidine-1-carboxylic acid tert-butyl ester (500 mg; 1.79 mmol) in 5 ml of acetonitrile was cooled to −5° C., iodoethane (308 mg, 1.79 mmol) and sodium hydride (96 mg, 3.59 mmol) were added; the reaction mixture was allowed to warm to room temperature and stirred for 72 h.

The reaction mixture was concentrated under vacuum; the residue was dissolved in ethyl acetate and washed with an aqueous saturated sodium bicarbonate solution and then with water.

The organic phase was dried over sodium sulfate, filtered and concentrated under vacuum. The crude product was purified by flash chromatography (Isolute silica gel cartridge: 10 g, eluent: dichloromethane) to obtain 332 mg (1.1 mmol) of the desired compound.

To a solution of intermediate 12 (330 mg, 1.1 mmol) in 20 ml of 1,4-dioxane, a 4M solution of hydrochloric acid in 1,4-dioxane (4.06 ml, 16 mmol) was added dropwise; the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under vacuum to obtain 262 mg (1.1 mmol) of the desired compound.

trans-4-Azido-3-methoxy-piperidine-1-carboxylic acid tert-butyl ester (1.6 g, 6.24 mmol), Pd/C 10% (200 mg) and acetic acid (1.6 ml) were dissolved in 25 ml of methanol and the reaction mixture was stirred under hydrogen atmosphere (4 bar) for 3 h. The reaction mixture was filtered on a celite pad and concentrated under vacuum. The crude product was purified by flash chromatography (Biotage SP1 cartridge 65i, eluent: dichloromethane/methanol=95/5%). 900 mg (3.91 mol) of the desired compound were obtained.

Intermediate 14 (900 mg, 3.91 mmol) and N,N-diisopropylethylamine (0.86 ml, 5 mmol were dissolved in 25 ml of dichloromethane. The reaction mixture was cooled to 0° C. and methanesulfonylchloride (0.33 ml, 4.30 mmol) was added. The reaction mixture was stirred at 0° C. for 20 min, then, water was added. The organic phase was separated, washed with an aqueous saturated sodium bicarbonate solution, dried over sodium sulfate and concentrated under vacuum. The crude product was purified by flash chromatography (Isolute silica cartridge: 10 g, eluent: hexane/ethyl acetate=50/50%). 170 mg (0.55 mol) of the desired compound were obtained.

Intermediate 15a (350 mg, 1.13 mmol) and potassium carbonate (157 mg, 1.13 mmol) were dissolved and stirred in 15 ml of acetonitrile. A solution of iodomethane (0.071 ml, 1.13 mmol) in 5 ml of acetonitrile was added dropwise and the reaction mixture was warmed to 60° C. overnight. The reaction mixture was concentrated under vacuum and the crude product was dissolved in ethyl acetate. The organic phase was washed with an aqueous saturated sodium bicarbonate solution, separated, dried over sodium sulfate and concentrated under vacuum. 300 mg (0.93 mmol) of the desired compound were obtained and used in the next steps without further purification.

Intermediate 15a (170 mg, 0.55 mmol) in 2 ml of 1,4-dioxane was stirred at 10° C. A 4M solution of hydrochloric acid in 1,4-dioxane (8 ml, 32 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 5 h. The reaction mixture was concentrated under vacuum to obtain 115 mg (0.55 mmol) of the desired compound.

was synthesized in analogy to Intermediate 16a, starting from Intermediate 15b.

was synthesized in analogy to Intermediate 15a, starting from (3S,4R)-4-amino-3-methoxy-piperidine-1-carboxylic acid tert-butyl ester.

Intermediate 17 (660 mg, 2.14 mmol) in 10 ml of 1,4-dioxane was stirred at 10° C. Trifluoroacetic acid (2 ml, 26 mmol) was added dropwise and the reaction mixture was stirred at room temperature 18 h. The reaction mixture was concentrated under vacuum to obtain 600 mg (1.86 mmol) of the desired compound, used in the next step without further purification.

N-methyl-N-piperidin-4-yl-methanesulfonamide hydrochloride (11 g, 47.91 mmol) was suspended in 200 ml of 1,2-dichloroethane, N,N-diisopropylethylamine (17.12 ml, 96.17 mmol) and 1-(tert-butoxycarbonyl)-piperidin-4-one (9.58 g, 48.08 mmol) were added and the reaction mixture was stirred at room temperature for 30 min Sodium triacetoxyborohydride (12.23 g, 57.50 mmol) was added and the reaction mixture was stirred at room temperature for 72 h. The reaction mixture was diluted with dichloromethane and washed with an aqueous saturated sodium bicarbonate solution.

The organic phase was dried over sodium sulfate and concentrated under vacuum. The crude product was purified by flash chromatography (Biotage SP1; silica gel cartridge: 65i; eluent: ethyl acetate/methanol=50/50%) to obtain 7.2 g (19.2 mmol) of the desired compound.

Intermediate 19a (7.2 g, 19.2 mmol) was suspended in 20 ml of 1,4-dioxane, a 4M solution of hydrochloric acid (48 ml, 192 mmol) in 1,4-dioxane was added dropwise. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under vacuum. 6.3 g (18 mmol) of the desired compound were obtained.

The following intermediates were synthesized in analogy to Intermediates 19a and 20a.

Carba- Di- mate amino Starting Starting Inter- Inter- ketone amine mediate STRUCTURE mediate STRUCTURE 1-(tert- butoxy- carbon- yl)- 4-oxo- piper- idine Ethane- sulfonic acid methyl- piper- idin-4- yl- amide 19b

20b

1-(tert- butoxy- carbon- yl)- 4-oxo- piper- idine (R)-N- Pyrrol- idin- 3-yl- methane sulfon- amide 19c

20c

1-(tert- butoxy- carbon- yl)- 4-oxo- piper- idine (S)-N- Pyrrol- idin- 3-yl- methane sulfon- amide 19d

20d

1-(tert- butoxy- carbon- yl)- 4-oxo- piper- idine Ethane- sulfonic acid piper- idin-4- yl- amide 19e

20e

1-(tert- butoxy- carbon- yl)- 4-oxo- piper- idine Piper- idine-4- carbox- ylic acid methyl amide 19f

20f

1-(tert- butoxy- carbon- yl)- 4-oxo- piper- idine Piper- idine-4- sulfonic acid methyl amide 19g

20g

1-(tert- butoxy- carbon- yl)- 4-oxo- piper- idine (R)-Pyr- rolidine- 3-car- boxilic acid methyl- amide 19h

20h

1-(tert- butoxy- carbon- yl)- 4-oxo- piper- idine (S)-Pyr- rolidine- 3-car- boxilic acid methyl- amide 19i

20i

1-(tert- butoxy- carbon- yl)- 4-oxo- piper- idine (S)-Pyr- rolidine- 3-car- boxilic acid amide 19j

20j

1-(tert- butoxy- carbon- yl)- 4-oxo- piper- idine 16a 19k

20k

1-(tert- butoxy- carbon- yl)- 4-oxo- piper- idine (R)-Pyr- rolidine- 3-car- boxilic acid amide 19l

20l

1-(tert- butoxy- carbon- yl)- 4-oxo- piper- idine 47b 19lf

20lf

1-(tert- butoxy- carbon- yl)- 4-oxo- piper- idine 47c 19lg

20lg

4-Methylamino-piperidine-1-carboxylic acid tert-butyl ester (500 mg, 1.87 mmol) was suspended in 10 ml of 1,2-dichloroethane. Tetrahydro-pyran-4-one (0.17 ml, 1.87 mmol) was added and the reaction mixture was stirred at room temperature for 30 min Sodium triacetoxyborohydride (593 mg, 2.80 mol) was added and the reaction mixture was stirred for 18 h. The reaction mixture was diluted with dichloromethane and washed with an aqueous saturated sodium bicarbonate solution.

The organic phase was dried over sodium sulfate and concentrated under vacuum. The crude product was purified by flash chromatography (Isolute silica gel cartridge 10 g; eluent: dichloromethane/methanol=94/6%). 240 mg (0.80 mmol) of the desired compound were obtained.

Intermediate 191a (240 mg, 0.80 mmol) was suspended in 10 ml of 1,4-dioxane, a 4M solution of hydrochloric acid (2.0 ml, 8.0 mmol) in 1,4-dioxane was added dropwise. The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated under vacuum. 200 mg (0.74 mmol) of the desired compound were obtained.

The following intermediates were synthesized in analogy to Intermediates 191a and 201a

Carbamate Amino Starting Starting Inter- Inter- amine ketone mediate STRUCTURE mediate STRUCTURE 4- Methyl- amino- piper- idine-1- carbox- ylic acid tert-butyl ester 3- Methoxy- tetra- hydro- pyran-4- one 19lb

20lb

4- Methyl- amino- piper- idine-1- carbox- ylic acid tert-butyl ester 2,6- dimethyl- tetra- hydro- pyran- 4-one 19lc

20lc

4- Methyl- amino- piper- idine-1- carbox- ylic acid tert-butyl ester 4,4- difluoro- cyclo- hexanone 19ld

20ld

4-amino- piper- idine-1- carbox- ylic acid tert-butyl ester 3- Methoxy- tetra- hydro- pyran- 4-one 19le

20le

N-methyl-N-piperidin-4-yl-methanesulfonamide hydrochloride (1.13 g, 4.95 mmol) was suspended in 10 ml of 1,2-dichloroethane, N,N-diisopropylethylamine (2.6 ml, 14.9 mmol) and N-carbethoxy-3-methoxy-piperidin-4-one (1 g, 4.95 mmol) were added and the reaction mixture was stirred at room temperature for 30 min Sodium triacetoxyborohydride (3.16 g, 14.85 mol) was added and the reaction mixture was stirred at room temperature for 72 h. The reaction mixture was diluted with dichloromethane and washed with an aqueous saturated sodium bicarbonate solution.

The organic phase was dried over sodium sulfate and concentrated under vacuum. 1.5 g (3.97 mmol) of the desired compound were obtained and used without further purification.

Intermediate 19m (1.5 g, 3.97 mmol) and potassion hydroxide (4.46 g, 7.94 mmol) were suspended in 25 ml of ethanol and the reaction mixture was stirred under reflux overnight.

The reaction mixture was concentrated under vacuum and the crude product was loaded on a SCX cartridge (25 g) and eluted with a 2M solution of ammonia in methanol. 1.2 g (3.97 mmol) of the desired compound were obtained.

Piperidin-4-yl-carbamic acid tert-butyl ester (6 g, 30 mmol) and 1-(benzyloxycarbonyl)-4-oxopiperidine (9.6 g, 48 mmol) were dissolved in 50 ml of dichloromethane and the reaction mixture was stirred at room temperature for 30 min; sodium triacetoxyborohydride (12.23 g, 57.5 mmol) was added and the reaction mixture was stirred at room temperature overnight.

The reaction mixture was diluted with dichloromethane and washed with an aqueous saturated sodium bicarbonate solution. The organic phase was dried over sodium sulfate and concentrated under vacuum. The crude product was treated with acetone/isopropyl ether and the precipitate obtained was filtered off. 8.4 g (20 mmol) of the desired product were obtained.

To a solution of intermediate 2l (8.4 g, 20 mmol) in 150 ml of 1,4-dioxane previously cooled to 0° C., 12.6 ml (50 mmol) of a 4M solution of hydrochloric acid in 1,4-dioxane were added dropwise; the reaction mixture was allowed to warm to room temperature and was stirred at that temperature overnight. The solid precipitated from the reaction mixture was filtered off and dried at 50° C. under vacuum to obtain 6 g (15 mmol) of the desired compound.

Intermediate 22 (6.0 g, 15 mmol) was suspended in 55 ml of dichloromethane; triethylamine (6.43 ml, 46 mmol) was added and the reaction mixture was cooled to 0° C. and stirred at that temperature for 30 min Methanesulfonyl chloride (1.43 ml, 18 mmol) in 5 ml of dichloromethane was added dropwise. The reaction mixture was stirred at 0° C. for 1 h; then water was added and the reaction mixture was extracted with dichloromethane. The organic phase was washed with an aqueous saturated sodium bicarbonate solution, with brine, dried over sodium sulfate and concentrated under vacuum. The crude product was treated with diisopropyl ether, the precipitate was filtered off and dried. 5 g (13 mmol) of the desired product were obtained.

Intermediate 23 (5 g, 13 mmol) was dissolved in 50 ml of methanol; acetic acid (1.5 ml, 25.3 mmol) and Pd/C 10% (500 mg) were added in sequence and the reaction mixture was stirred under a hydrogen atmosphere (3 bar) at room temperature for 5 days. The reaction mixture was filtered on a celite pad and the organic phase was loaded on a SCX cartridge (10 g). After washing with methanol, the desired compound was eluted with a 2M solution of ammonia in methanol. 3.7 g (4.6 mmol) of the title compound were obtained.

Intermediate 24 (1.1 g, 4.21 mmol) was suspended in 20 ml of dry dichloromethane, N,N-diisopropylethylamine (1.47 ml, 8.42 mmol) and DMF (137 μl, 1.67 mmol) were added and the reaction mixture was stirred under nitrogen atmosphere and cooled to 0° C. Intermediate 2a (812 mg, 4.21 mmol) in 5 ml of dichloromethane was added dropwise and the reaction mixture was allowed to warm up to room temperature and stirred for 1.5 h; the reaction mixture was diluted with dichloromethane and washed with an aqueous saturated sodium bicarbonate solution. The organic phase was separated, dried over sodium sulfate and concentrated under vacuum. The crude product was purified by flash chromatography (isolute silica gel cartridge: 10 g; eluent: dichloromethane/methanol=95/5%). 1.0 g (2.41 mmol) of the title compound were obtained.

The following intermediates were synthesized in analogy to Intermediate 25a.

Core Piperidine Chloro- Inter- Inter- pyrimidine mediate mediate Intermediate STRUCTURE 2a 20a  25b

2a 20b  25c

2a 20f  25d

2a 20h  25e

2a [1,4′]-Bipiper- idinyl-4-ol 25f

2a 4-Methoxy- [1,4′]bi- piperidinyl 25g

2a 4-Piperidin-4- yl-morpholine 25h

2a [1,4′]Bi- piperidinyl 25i

2a [1,4′]-Bi- piperidinyl- 3-ol 25j

2b 24  25k

2b 20a  251

2b [1,4′]-Bi- piperidinyl- 4-ol 25m

2c 20a  25n

2a 20le 25o

Intermediate 3a (10 g, 49.35 mmol) and N,N-diisopropylethylamine (17 ml, 99 mmol) were dissolved in 20 ml of dry DMF; 2-(3,4-dichloro-phenyl)-ethylamine (9.57 g, 49.35 mmol) in 10 ml of dry DMF was added and the reaction mixture was stirred at 90° C. for 2 h. The reaction mixture was cooled to room temperature, water was added and the reaction mixture was extracted with dichloromethane; the organic phase was concentrated under vacuum, the crude product was suspended and stirred in diethyl ether and the precipitate was filtered off and dried. 10.2 g (28.8 mmol) of the desired compound were obtained.

Intermediate 26a (10.0 g, 28.25 mmol) was dissolved in 70 ml of ethanol and a solution of LiOH (3.52 g, 83.88 mmol) in 70 ml of water was added. The reaction mixture was stirred at 70° C. for 1 hour, concentrated under vacuum and the remaining aqueous solution was acidified by 20 ml of 4M solution of hydrochloric acid in 1,4-dioxane; the precipitate formed was filtered off and dried. 8.6 g (26.37 mmol) of the desired product were obtained.

The following intermediates were synthesized in analogy to Intermediates 26a and 27a.

Core Ester Acid Inter- Inter- Inter me- me- me- diate Amine diate STRUCTURE diate STRUCTURE 3a 3,4- Dichloro- benzyl- amine 26b 

27b

3b 4-tert- butyl- benzyl- amine 26c 

27c

3a biphenyl- 3- ylmethan- amine 26d 

27d

3b 4-tert- butyl- benzyl- amine 26e 

27e

3c 2-(3,4- dichloro- phenyl)- ethyl- amine 26f 

27f

3c biphenyl- 3- yl-methan- amine 26g 

27g

3d biphenyl- 3- yl-methan- amine 26h 

27h

3a Inter- mediate 7c 26ha

27ha

3d Inter mediate 7c 26hb

27hb

3a Inter- mediate 7p 26hc

27hc

3a Inter- mediate 7q 26hd

27hd

3a Inter- mediate 7t 26he

27he

3a Inter- mediate 7v 26hf

27hf

3b Inter- mediate 7t 26hr

27hr

3b Inter- mediate 7v 26hs

27hs

Intermediate 3d (2 g, 7.53 mmol) and N,N-diisopropylethylamine (1.97 ml, 11.3 mmol) were dissolved in 15 ml of dry DMF; 4-tertbutyl-benzylamine (1.6 ml, 9.04 mmol) was added and the reaction mixture was stirred at 60° C. for 18 h. The reaction mixture was cooled to room temperature, water was added and the reaction mixture was extracted with dichloromethane; the organic phase was concentrated under vacuum and the crude product was purified by flash chromatography (BIOTAGE SP1; silica gel cartridge: 65i; eluent: hexane/ethyl acetate=70/30%). 1.5 g (3.82 mmol) of the desired compound were obtained.

Intermediate 26hb (75 mg, 179 μmol), tributyl(vinyl)tin (200 μl, 685 μmol) and bis(triphenylphosphine)palladium chloride (13 mg, 18 μmol) were added to 3 ml 1,2-dichloroethane. The reaction mixture was heated in the microwave for 4 h at 120° C. Then, the solvent was removed in vacuum and the residue was purified by reversed phase HPLC to give the desired product (56 mg, 117 mmol).

was synthesized in analogy to intermediate 26ib, starting from intermediate 26hb and tributyl(ethynyl)tin.

Intermediate 26i (500 mg, 1.27 mmol) and CuCN (114 mg, 1.27 mmol) were dissolved in 5 ml of DMA and the reaction mixture was stirred at 100° C. overnight. The reaction mixture was cooled, diluted with dichloromethane and the organic phase was washed with water, dried over sodium sulfate and concentrated under vacuum. 30 mg (0.1 mmol) of the crude product were obtained and used in the next step without purification.

was synthesized in analogy to 27a starting from intermediate 26ib.

was synthesized in analogy to 27a starting from intermediate 26ic.

Intermediate 27a (4 g, 12.14 mmol), TBTU (3.9 g, 12.14 mmol) and N,N-diisopropylethylamine (5.34 ml, 30.35 mmol) were dissolved in 25 ml of DMF. The reaction mixture was stirred under nitrogen atmosphere at room temperature for 30 min; then piperidin-4-one hydrochloride (1.66 g, 12.14 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under vacuum and the crude product was dissolved in dichloromethane. The organic phase was washed with a saturated aqueous solution of sodium bicarbonate, with a 1M aqueous solution of sodium hydroxide, with brine, then dried over sodium sulfate, filtered and concentrated under vacuum. The crude product was purified by flash chromatography (BIOTAGE SP1; silica gel cartridge: 65i; eluent: dichloromethane/methanol=95/5%). 2.2 g (5.4 mmol) of the desired compound were obtained.

The following intermediates were synthesized in analogy to intermediate 28a.

Acid Intermediate Amine Intermediate STRUCTURE 27b Piperidin-4-one 28b

27c Piperidin-4-one 28c

27d Piperidin-4-one 28d

27g Piperidin-4-one 28e

27c Azepan-4-one 28f

27e Piperidin-4-one 28g

Intermediate 28a (500 mg, 1.22 mmol), piperazine-1-carboxylic acid tert-butyl ester (228 mg, 1.23 mmol) and 2-picoline borane complex (131.3 mg, 1.22 mmol) in 15 ml of methanol were stirred at room temperature for 72 h; the reaction mixture was concentrated under vacuum and the crude product was dissolved in dichloromethane. The organic phase was washed with water, dried over sodium sulfate, filtered and concentrated under vacuum. The crude product was purified by flash chromatography (Isolute silica gel cartridge: 20 g; eluent: dichloromethane/methanol=98/2%). 280 mg (0.48 mmol) of the desired compound were obtained.

Intermediate 29 (280 mg, 0.48 mmol) was dissolved in 6 ml of 1,4-dioxane; 4 ml (16 mmol

of a 4M solution of hydrochloric acid in 1,4-dioxane were added dropwise and the reaction mixture was stirred at room temperature overnight. The solvent was concentrated under vacuum. 240 mg (0.46 mmol) of the desired compound were obtained.

Intermediate 27c (500 mg, 1.67 mmol), TBTU (643 mg, 2 mmol) and N,N-diisopropylethylamine (0.29 ml, 1.67 mmol) were dissolved in 5 ml of DMF. The reaction mixture was stirred under nitrogen atmosphere at room temperature for 10 min; then [1,4]diazepan-1-carboxylic acid tert-butyl ester (334 mg, 1.67 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and washed with an aqueous saturated solution of sodium bicarbonate. The organic phase was separated, dried over sodium sulfate and concentrated under vacuum. The crude product was suspended in diisopropyl ether and stirred, the solid obtained was filtered and dried. 700 mg (1.45 mmol) of the desired compound were obtained.

Intermediate 31 (600 mg; 1.24 mmol) was suspended in 5 ml of diethyl ether, 5 ml of a 1M solution of hydrochloric acid in diethyl ether was added dropwise and the reaction mixture was stirred at room temperature overnight. The solvent was concentrated under vacuum and the crude product was loaded on a SCX cartridge (10 g) and eluted with a 2M solution of ammonia in methanol. 470 mg (1.23 mmol) of the title compound were obtained.

Intermediate 3a (1.5 g, 7.47 mmol) and tetrakis(triphenylphosphine)palladium (143.9 mg, 0.12 mmol) were suspended in 40 ml of toluene under nitrogen atmosphere; 4-tert-butyl-benzylzinc bromide (29.9 ml, 15 mmol) was added dropwise and then the reaction mixture was stirred at 20° C. for 8 h. 5 ml of methanol, 40 ml of water and 100 ml of dichloromethane were added. The organic phase was separated, dried over sodium sulfate and concentrated under vacuum. The crude product obtained was purified by flash chromatography (Biotage column 40M+; eluent: dichloromethane/ethyl acetate=95/5%). 230 mg (0.74 mmol) of the desired compound were obtained.

To a solution of 4-tert-butylphenylacetylene (5 ml, 28 mmol) in 20 ml of dry tetrahydrofuran under nitrogen atmosphere, a solution of catecholborane (3.41 ml, 31 mmol) in 20 ml of dry tetrahydrofuran was added dropwise. The reaction mixture was refluxed for 2 h and then concentrated under vacuum; the crude product obtained was dissolved in ethyl acetate and the organic phase was washed with a 2 M aqueous solution of hydrochloric acid. The organic phase was separated, washed with brine, dried over sodium sulfate and concentrated under vacuum. The crude product obtained was purified by flash chromatography (Biotage column 40M+; eluent: dichloromethane/ethyl acetate=95/5%). 230 mg (0.82 mmol) of the desired compound were obtained.

Intermediate 3a (600 mg, 3 mmol), intermediate 34 and tetrakis(triphenylphosphine)palladium (347 mg, 0.3 mmol) were dissolved in 3.6 ml of a 2 M aqueous solution of sodium carbonate and 40 ml of 1,2 dimethoxyethane. The reaction mixture was stirred at 80° C. overnight. Water was added and the reaction mixture was extracted with dichloromethane. The organic phase was separated, dried over sodium sulfate and concentrated under vacuum. The crude product obtained was purified by flash chromatography (Biotage column 40M+; eluent: dichloromethane/ethyl acetate=95/5%). 550 mg (1.60 mmol) of the desired compound were obtained.

Intermediate 35 (250 mg, 0.77 mmol) was dissolved in 5 ml of ethanol and 5 ml of tetrahydrofuran. Pd/C (35 mg) was added and the reaction mixture was stirred under hydrogen atmosphere (1 atm) at room temperature overnight. The reaction mixture was filtered on a celite pad and concentrated under vacuum. 170 mg (0.52 mmol) of the desired compound were obtained.

Palladium acetate (170 mg, 0.75 mmol) and 2,2′-bis(diphenylphosphino)-1,1′-binapthyl (936 mg, 1.5 mmol) were dissolved in 25 ml of 1,4-dioxane and stirred at 40° C. for 30 minutes. 2-chloro-3-methylpyridine-4-carboxylic acid ethyl ester (500 mg, 2.5 mmol), 3,4-dichlorobenzylamine (680 mg, 5 mmol) and cesium carbonate (715.5 mg, 3.76 mmol) were added and the reaction mixture was refluxed for 48 h. The solvent was concentrated under vacuum and the crude product was loaded on a SCX cartridge (10 g) and eluted with a 2M solution of ammonia in methanol. The solvent was concentrated under vacuum and the crude product obtained was purified by flash chromatography (Biotage column 25M+; eluent: ethyl acetate). 250 mg (0.73 mmol) of the desired compound were obtained.

3-(Bromomethyl)biphenyl (150 mg, 0.58 mmol), sodium carbonate (188 mg, 1.75 mmol) and 3-amino-2-methyl-benzoic acid ethyl ester (0.1 ml, 0.58 mmol) were mixed in 2 ml of DMF and stirred at 100° C. for 2 hours. The solvent was then concentrated under vacuum and the crude product was purified by reverse phase preparative HPLC. 131 mg (0.37 mmol) of the desired compound were obtained.

Intermediate 35 (300 mg, 0.92 mmol) was dissolved in 4 ml of ethanol and 4 ml of water. Lithium hydroxide (194 mg, 4.7 mmol) was added and the reaction mixture was stirred at 70° C. for 2 h, concentrated under vacuum and the remaining aqueous solution was acidified by 10 ml of a 4M solution of hydrochloric acid in 1,4-dioxane and extracted with dichloromethane; the organic phase was separated, washed with brine, dried over sodium sulfate and concentrated under vacuum. 250 mg (0.84 mmol) of the desired product were obtained.

The following intermediates were synthesized in analogy to intermediate 39a

Ester Intermediate Acid Intermediate STRUCTURE 33 39b

36 39c

37 39d

38 39e

Intermediate 27c (660 mg, 2.20 mmol), TBTU (849 mg, 2.65 mmol) and N,N-diisopropylethylamine (0.57 ml, 3.31 mmol) were dissolved in 25 ml DMF. The reaction mixture was stirred under nitrogen atmosphere at room temperature for 10 min; then piperidin 4-yl carbamic acid tert-butyl ester (441 mg, 2.20 mmol) was added and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with dichloromethane and washed with an aqueous saturated solution of sodium bicarbonate. The organic phase was separated, dried over sodium sulfate and concentrated under vacuum. The crude product was purified by flash chromatography (Biotage SNAP column 50 g; eluent: dichloromethane/methanol=90/10%). 990 mg (2.05 mmol) of the desired compound were obtained.

Intermediate 40a (990 mg, 2.05 mmol) was suspended in 50 ml of 1,4-dioxane, a 4M solution of hydrochloric acid (8.5 ml, 34 mmol) in 1,4-dioxane was added dropwise. The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated under vacuum. 780 mg (18 mmol) of the desired compound were obtained.

The following intermediates were synthesized in analogy to Intermediates 40a and 41a.

Carba- Amine mate Starting Starting Inter- inter- acid amine mediate STRUCTURE mediate STRUCTURE Inter- mediate 27ha piperidin 4-yl carba- mic acid tert-butyl ester 40b

41b

4,4-Difluorocyclohexanone (500 mg, 3.73 mmol) and potassium hydroxide (502 mg, 8.95 mmol) were dissolved in 10 ml of methanol. The reaction mixture was cooled to 0° C. and a solution of iodine (1.04 g, 4.10 mmol) in 20 ml of methanol was added dropwise within 1 h. The reaction mixture was stirred at room temperature for 18 h, and then concentrated under vacuum. The crude product was stirred in 10 ml of dichloromethane and the precipitate was filtered off. The filtrate was concentrated under vacuum and 480 mg of the desired product (2.45 mmol) were obtained as an oil.

Sodium hydride (196 mg, 4.89 mmol) was suspended in 10 ml of tetrahydrofurane. The reaction mixture was cooled to 0° C. and a solution of Intermediate 42 (480 mg, 4.45 mmol) in 5 ml of tetrahydrofurane was added dropwise. The reaction mixture was stirred at 0° C. for 1 h, then iodomethane (0.305 ml, 4.89 mmol) was added. The reaction mixture was stirred at room temperature for 4 h. 0.1 ml of a 37% aqueous solution of hydrochloric acid and 0.1 ml of water were added, then additional 0.3 ml of a 37% aqueous solution of hydrochloric acid were added. The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated under vacuum and 400 mg (2.44 mmol) of the desired product were obtained as an oil.

Iodomethane (3.48 ml, 55.88 mmol) was dissolved in 250 ml of tetrahydrofurane, the reaction mixture was stirred at 0° C. under nitrogen atmosphere and sodium hydride (60% on mineral oil, 2.23 mg, 5.88 mmol) was added. After 15 minutes, trans 4-azido-tetrahydropyran-3-ol (4.0 g, 27.94 mmol) was added and the reaction mixture was allowed to reach room temperature and stirred for 18 h. 50 ml of water were added, the organic phase was separated, dried over sodium sulphate and concentrated under vacuum. The crude oil obtained was purified by flash chromatography (Biotage SNAP column 100 g; eluent: dichloromethane/ethyl acetate=80/20%). 200 mg (1.27 mmol) of the desired regioisomer were obtained as trans racemate (relative configuration assigned by NMR).

Intermediate 44 (200 mg, 1.27 mmol) was dissolved in 250 ml of methanol, Pd/C (50 mg was added and the reaction mixture was stirred under hydrogen atmosphere (4 bar) for 18 h. The reaction mixture was filtered on a celite pad and the organic phase was concentrated under vacuum. 110 mg (0.84 mmol) of the desired product were obtained as trans racemate.

3-Methoxy-tetrahydro-pyran-4-one (500 mg, 3.84 mmol), benzylamine (0.42 ml, 3.84 mmol) and Raney-Nickel (100 mg) were suspended in 20 ml of dry ethanol and the reaction mixture was stirred under hydrogen atmosphere (4.5 bar) for 3 days. The reaction mixture was filtered on a celite pad and the organic phase was concentrated under vacuum. The crude product obtained was dissolved in 10 ml of methanol, loaded on a SCX cartridge (10 g) and eluted with a 2M solution of ammonia in methanol. The solvent was concentrated under vacuum and the crude product obtained was purified by flash chromatography (Isolute cartridge 10 g; eluent: dichloromethane/methanol=96/4%). 163 mg (0.73 mmol) of the desired product were obtained as cis racemate (relative configuration assigned by NMR).

3-Methoxy-tetrahydro-pyran-4-one (1 g, 7.68 mmol), (R)-(+)-1-phenylethylamine (0.99 ml, 7.68 mmol) and Raney-Nickel (200 mg) in 10 ml dry ethanol were stirred under a hydrogen atmosphere (5 bar) for 15 days. The reaction mixture was diluted with 20 ml of methanol and 20 ml of tetrahydrofurane, stirred for 15 minutes, filtered on a celite pad and concentrated under vacuum. The crude product was loaded on a SCX cartridge (50 g). The cartridge was washed with methanol and the desired product was eluted with a 7 M solution of ammonia in methanol. The basic organic phase was concentrated under vacuum and the crude product obtained was purified by flash chromatography (dichloromethane/methanol=98/2%) to obtain 710 mg (3.02 mmol) of the desired product as single stereoisomer (diastereoisomeric purity confirmed and relative cis stereochemistry assigned by NMR).

was synthesised in analogy to Intermediate 46b, starting from 3-Methoxy-tetrahydro-pyran-4-one and (S)-(−)-1-phenylethylamine (diastereoisomeric purity confirmed and relative cis stereochemistry assigned by NMR).

Intermediate 46a (163 mg, 0.73 mmol) was dissolved in 10 ml of methanol, Pd/C (50 mg) was added and the reaction mixture was stirred under hydrogen atmosphere (4.5 bar) for 18 h. The reaction mixture was filtered on a celite pad and the organic phase was concentrated under vacuum. 80 mg (0.61 mmol) of the desired product were obtained as cis racemate.

Intermediate 46b (1.18 g, 5.01 mmol), Pd/C 10% (200 mg) and acetic acid (0.3 ml, 5.01 mmol) in 20 ml of methanol were stirred under a hydrogen atmosphere (5 bar) for 18 h. The reaction mixture was diluted with 20 ml of methanol, stirred for 15 minutes, filtered on a celite pad and concentrated under vacuum. The crude product was loaded on a SCX cartridge (50 g). The cartridge was washed with methanol and the desired product was eluted with a 7 M solution of ammonia in methanol. The basic organic phase was concentrated under vacuum and 513 mg (3.91 mmol) of the desired product were obtained as single stereoisomer.

was synthesised in analogy to Intermediate 47b, starting from Intermediate 46c

Intermediate 47b was stirred in diethyl ether and a 2M solution of hydrochloric acid in diethyl ether was added drop-wise until a white solid was formed. The reaction mixture was concentrated under vacuum, the crude product was suspended in methanol and the reaction mixture was concentrated under vacuum to give the desired hydrochloride.

was synthesised in analogy to Intermediate 48b, starting from Intermediate 47c.

3-(trifluoromethyl)benzaldehyde (6.46 ml, 48.24 mmol) was dissolved in 80 ml of dry tetrahydrofurane, the reaction mixture was cooled to −78° C. and a 0.5M solution of 3-butenylmagnesiumbromide in tetrahydrofurane (106.13 ml, 53.06 mmol) was added dropwise over 30 minutes. The reaction mixture was stirred at −78° C. for 30 minutes. Then, the reaction mixture was allowed to reach room temperature and stirred 18 h. Then, 100 ml of a saturated aqueous solution of ammonium chloride and 200 ml of ethyl acetate were added. the organic layer was separated, dried over sodium sulfate and concentrated under vacuum. 7.75 g (33.69 mmol) of the desired product were obtained.

Intermediate 49a was dissolved in 70 ml of dry dichloromethane, the reaction mixture was stirred under nitrogen atmosphere at 0° C. and N-bromosuccinimide was added. The reaction mixture was allowed to reach room temperature and stirred for 48 h. The reaction mixture was concentrated under vacuum. The crude product was purified by flash chromatography (Isolera cartridge eluent: hexane/ethyl acetate=90/10%) to obtain the desired product as diastereoisomeric mixture.

Intermediate 50a was purified by flash chromatography (Isolera cartridge; eluent: hexane/ethyl acetate=98/2%). 2.3 g (7.44 mmol) of the trans diastereoisomer were obtained as racemic mixture (relative stereochemistry assigned by NMR).

Further elution of the column gave 1.05 g (3.39 mmol) of the cis diastereoisomer as racemic mixture (relative stereochemistry assigned by NMR).

The following intermediates were synthesized in analogy to Intermediates 49a, 50a, 51a and 52a

Starting aldehyde Intermediate STRUCTURE 3-Methyl- benzaldheyde 49b

50b

51b

52b

4-Methyl- benzaldheyde 49c

50c

51c

52c

4-Fluoro-3- methyl- benzaldheyde 49d

50d

51d

52d

3-Fluoro-4- methyl- benzaldheyde 49e

50e

51e

52e

4-Chloro- benzaldheyde 49f

50f

51f

52f

4-Trifluoro- methyl- benzaldheyde 49g

50g

51g

52g

Intermediate 50a (1.7 g, 5.49 mmol) was dissolved in 5 ml of DMSO and the reaction mixture was stirred under nitrogen atmosphere at room temperature. Phthalimide potassium salt (2.54 g, 13.75 mmol) and sodium iodide (240 mg, 1.60 mmol) were added and the reaction mixture was stirred at 70° C. for 18 h. The reaction mixture was cooled to room temperature and diluted with 40 ml of a saturated aqueous sodium bicarbonate solution and with 100 ml of ethyl acetate. The organic layer was separated, dried on sodium sulfate and concentrated under vacuum. The crude product was purified by flash chromatography (Isolera cartridge; eluent: hexane/ethyl acetate=85/15%) to yield 1.2 g (3.2 mmol) of the phthalimido intermediate. The phthalimido intermediate (1.2 g, 3.2 mmol) was dissolved in 15 ml of methanol. Hydrazine hydrate (1.24 ml, 25.60 mmol) was added and the reaction mixture was stirred at room temperature for 48 h. The reaction mixture was concentrated under vacuum. The crude product was dissolved in 10 ml of dichloromethane, the organic layer was washed with water, separated, dried on sodium sulfate and concentrate under vacuum. 474 mg (1.93 mmol) of the desired product were obtained.

was synthesized in analogy to Intermediate 53a starting from intermediate 51a

was synthesized in analogy to Intermediates 53a starting from intermediate 52a.

The following intermediates were synthesized in analogy to Intermediates 53a, 54a and 55a.

Starting Starting Inter- Inter- inter- Inter- mediate mediate STRUCTURE mediate mediate STRUCTURE 50b 53b

51b 54b

50c 53c

51c 54c

50d 53d

51d 54d

50e 53e

51e 54e

50f 53f

51f 54f

50g 53g

51g 54g

2-bromo- methyl- 4-phenyl- tetra- hydro- furan 53h

52e 55e

52b 55b

52f 55f

52c 55c

52g 55g

52d 55d

2,3-Dihydro-pyrano[3,2-b]pyridine-4one (250 mg, 1.7 mmol) and Raney-Nickel (25 mg) were added to a solution of ammonia in ethanol (10 ml) and the reaction mixture was stirred under hydrogen atmosphere (3 bar) for 18 h at room temperature. Then, the catalyst was removed by filtration on a celite pad and the mixture was concentrated under vacuum. The residue was purified by reversed phase HPLC to give the desired product (129 mg, 600 μmol).

Synthesis of Examples

E and G within the scope of this invention denotes C or N, preferred nitrogen.

The examples of this invention are synthesized according to the following general synthetic procedures:

Synthetic Procedure A

Examples: 1-159gc; 289-302 Synthetic Procedure B

Examples: 160-247; 228a; 228ga-228gn; 229-247

Examples: 286-288

Examples: 228b-228g; 228go; 228gp Synthetic Procedure C

Examples: 248-283; 275a-275dj

Example 1

Intermediate 25b (70 mg, 0.16 mmol), 4-tert-butyl-benzylamine (32 mg, 0.19 mmol) and N,N-diisopropyl-ethyl amine (0.042 ml, 0.24 mmol) in 2 ml of dry 1,4-dioxane were stirred at 70° C. overnight. The reaction mixture was concentrated under vacuum and the crude product was dissolved in dichloromethane. The organic phase was washed with a saturated aqueous sodium bicarbonate solution, dried over sodium sulfate and concentrated under vacuum. The crude product was purified by flash chromatography (Silica Isolute cartridge 5 g; eluent: ethyl acetate/methanol=90/10%). 16 mg (0.027 mmol) of the desired product were obtained.

HPLC (Method 2F): R_(t). (min)=7.59

[M+H]⁺=557

The following examples were synthesized in analogy to the preparation of Example 1.

Ex Inter- me- HPLC Meth- # STRUCTURE diate Amine [M + H]⁺ R_(t•)(min) od  2

25i 2-(3,4- dichloro- phenyl)- ethyl- amine 476 7.98 1E  3

25f 2-(3,4- dichloro- phenyl)- ethyl- amine 492 2.91 B  4

25f 3- trifluoro methyl- benzyl- amine 478 6.77 1E  5

25f 4- trifluoro- methoxy- benzyl- amine 494 6.78 1E  6

25f 3-fluoro- 5-trifluoro methyl- benzyl- amine 496 6.73 1E  7

25f 4-tert- butyl- benzyl- amine 466 7.45 1E  8

25f 3- trifluoro methoxy- benzyl- amine 494 7.08 1E  9

25f 4- trifluoro methyl- benzyl- amine 478 6.63 1E 10

25f 3-fluoro- 4-trifluoro methyl- benzyl- amine 496 6.85 1E 11

25f 2-(3- trifluoro methyl- phenyl)- ethyl- amine 492 7.23 1E 12

25f 2-(4- trifluoro methyl- phenyl)- ethyl- amine 492 7.37 1E 13

25f (4- (trifluoro- methyl)- cyclo- hexyl)- methan- amine 484 6.82 1E 14

25f 2-(4- trifluoro- methoxy- phenyl)- ethyl- amine 508 7.37 1E (Fu- sion) 15

25f 4-phenyl- butyl- amine 452 7.15 1E 16

25f 2- phenoxy- ethyl- amine 440 7.10 1E (Fu- sion) 17

25f 3-phenyl- propyl- amine 438 7.83 1E (Fu- sion) 18

25f 2-benzyl- oxy- ethyl- amine 454 5.83 1E (Hydro) 19

25f chroman- 3-yl- methan- amine 466 7.85 1E (Fu- sion) 20

25f (1- phenyl- pyrroli- din-3- yl)- methan- amine 479 7.05 1E (Hydro) 21

25f 2-fluoro- 4-tri- fluoro methyl- benzyl- amine 496 8.38 1E (Fu- sion) 22

25f 4-phenyl- cyclo- hexyl- amine 478 9.38 1E (Fu- sion) 23

25f indan-2- yl- methan- amine 450 6.55 1E (Hydro) 24

25f chroman- 3- ylamine 452 6.18 1E (Hydro) 25

25f (R)- (1,2,3,4- tetra- hydro- naphtalen- 2-yl)amine 450 7.08 1E (Hydro) 26

25f (1,2-di- hydro- cyclo- buta- benzen-1- yl)- methan- amide 436 6.93 1E (Hydro) 27

25f (2,3-di- hydro- benzo- furan-2- yl)- methan- amine 452 6.47 1E (Hydro) 28

25f Cyclo- hexyl- amine 402 4.90 1E 29

25f benzo- furan-5- ylmethan amine 450 6.73 1E (Hydro) 30

25f 3-chloro- 4- methyl- benzyl- amine 458 7.75 1E (Hydro) 31

25f 3,4-di- methyl- benzyl- amine 438 7.37 1E (Hydro) 32

25c 3-chloro- 4- methyl- benzyl- amine 563 6.98 2F 33

25c 3-chloro- 4-tri- fluoro methyl- benzyl- amine 617 9.47 1E (Hydro) 34

25c 4-iso- propyl- benzyl- amine 557 7.03 2F 35

25c 3,4-di- chloro- benzyl- amine 583 8.65 1E (Hydro) 36

25c 2-(3,4-di- chloro- phenyl)- ethyl- amine 597 9.72 1E (Hydro) 37

25c 4-tert- butyl- benzyl- amine 571 9.28 1E (Hydro) 38

25c 9a 598 1.45 2F 39

25c 4-chloro- 3-fluoro- benzyl- amine 567 8.82 1E (Hydro) 40

25c (1- phenyl- piperidin- 4yl)- methan- amine 598 8.98 1E (Hydro) 41

25c 9b 584 8.92 1E (Hydro) 42

25h 9a 479 8.67 1E (Hydro) 43

25h 3-chloro- 4- methyl- benzyl- amine 444 8.63 1E (Hydro) 44

25h 3-fluoro- 4- methyl- benzyl- amine 428 7.58 1E (Hydro) 45

25h 4-chloro- 3-fluoro- bemzyl- amine 448 7.88 1E (Hydro) 46

25h indan- 2yl- methan- amine 436 8.27 1E (Hydro) 47

25h 3-chloro- 4-tri- fluoro methyl- benzyl- amine 498 7.30 2F 48

25h 3,4- difluoro- benzyl- amine 432 4.20 2G 49

25b 4-chloro- benzyl- amine 535 7.38 2F 50

25h chroman- 3-yl- methan amine 452 7.85 1E (Hydro) 51

25h (1- phenyl- pyrroli- din-3-yl)- methan- amine 465 8.93 1E (Hydro) 52

25h 4-tert- butyl- benzyl- amine 452 7.18 2F 53

25b 2-(3,4- dichloro- phenyl)- ethyl- amine 583 7.97 1E (Hydro) 54

25b (6-tert- butyl- pyridin- 3-yl)- methan- amine 558 7.73 1E (Hydro) 55

25b 4-fluoro- 3- methyl- benzyl- amine 533 8.05 1E (Hydro) 56

25b 4-ethyl- benzyl- amine 529 8.35 1E (Hydro) 57

25b chroman- 3-yl- methan amine 557 7.62 1E (Hydro) 58

25b (1-phenyl- piperidin- 4yl)- methan- amine 584 8.05 1E (Hydro) 59

25b 3-chloro- 4- methyl- benzyl- amine 549 8.22 1E (Hydro) 60

25b (1- phenyl- pyrrolidin- 3-yl)- methan- amine 570  8.07- 8.47 1E (Hydro) 61

25b indan- 2yl- methan- amine 541 8.03 1E (Hydro) 62

25b 3-chloro- 4-tri- fluoro methyl- benzyl- amine 603 8.68 1E (Hydro) 63

25b 4-chloro- 3-fluoro- benzyl- amine 553 7.55 1E (Hydro) 64

25b 4-iso- propyl- benzyl- amine 543 6.82 2F 65

25b 3-fluoro- 4- methyl- benzyl- amine 533 8.57 1E (Hydro) 66

25b 3-chloro- benzyl- amine 535 6.72 2F 67

25b 4- methoxy- benzyl- amine 531 2.39 2F 68

25b 3-chloro- 4-fluoro- benzyl- amine 553 7.57 2F 69

25a 4-tert- butyl- benzyl- amine 543 7.97 1E (Hydro) 70

25a 4-tri- fluoro methoxy- benzyl- amine 585 7.63 1E (Hydro) 71

25a chroman- 3-yl- methan amine 543 6.75 1E (Hydro) 72

25a 3,4-di- chloro- benzyl- amine 555 7.30 1E (Hydro) 73

25a indan- 2yl- methan- amine 527 7.35 1E (Hydro) 74

25a (1- phenyl- pyrrolidin- 3-yl)- methan- amine 555  7.43- 7.80 1E (Hydro) 75

25a 3-chloro- 4-tri- fluoro methyl- benzyl- amine 589 7.78 2F 76

25a 4-chloro- 3-fluoro- benzyl- amine 539 2.07 1F 77

25e 3-chloro- 4-tri- fluoro methyl- benzyl- amine 539 8.23 1E (Hydro) 78

25e 4-chloro- 3-fluoro- benzyl- amine 489 7.33 1E (Hydro) 79

25l chroman- 3-yl- methan amine 571 8.13 1E (Hydro) 80

25l 4-chloro- 3-fluoro- benzyl- amine 567 8.36 1E (Hydro) 81

25l 3-chloro- 4-tri- fluoro methyl- benzyl- amine 617 9.12 1E (Hydro) 82

25l 3,4-di- chloro- benzyl- amine 583 8.83 1E (Hydro) 83

25l 4-tert- butyl- benzyl- amine 571 9.73 1E (Hydro) 84

25l (1- phenyl- pyrrolidin- 3-yl)- methan- amine 584  8.70- 9.02 1E (Hydro) 85

25l 9c 584 9.1  1E (Hydro) 86

25l indan- 2yl- methan- amine 555 8.80 1E (Hydro) 87

25l 9a 598 8.97 1E (Hydro) 88

25k 3,4-di- chloro- benzyl- amine 569 7.78 1E (Hydro) 89

25k 3-phenyl- cyclo- hexyl- amine 569 8.45 1E (Hydro) 90

25k chroman- 3-yl- methan amine 557 7.20 1E (Hydro) 91

25m 2-(3,4- dichloro- phenyl)- ethyl- amine 506 7.87 1E 92

25m 3,4- dichloro- benzyl- amine 492 7.62 1E 93

25d (1- phenyl- pyrrolidin- 3-yl)- methan- amine 520 7.70 1E (Hydro) 94

25g 4-iso- propyl- benzyl- amine 466 6.71 2F 95

25g 4-chloro- 3-fluoro- benzyl- amine 476 9.18 1E (Hydro) 96

25g (1-phenyl- piperidin- 4-yl)- methan- amine 507 9.55 1E (Hydro) 97

25g 9a 507 1.22 2F 98

25g 3-chloro- 4- methyl- benzyl- amine 472 9.62 1E (Hydro)

Example 99

Intermediate 2a (200 mg, 1.047 mmol) was dissolved in 30 ml of dichloromethane. [1,4′]Bipiperidinyl-4-ol (192 mg, 1.047 mmol) was added and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under vacuum and the crude product was dissolved in 1 ml of DMSO. Phenethylamine (0.6 ml, 4.73 mmol) and N,N-diisopropyl-ethyl amine (0.013 ml, 0.075 mmol) were added and the reaction mixture was stirred at 80° C. overnight. The reaction mixture was concentrated under vacuum. The crude product was purified by reverse phase preparative HPLC. 331 mg (0.616 mmol) of the desired product were obtained.

HPLC (Method C): R_(t). (min)=1.34

[M+H]⁺=424

The following examples were synthesized in analogy to the preparation of Example 99.

HPLC Ex Inter- R_(t•) # STRUCTURE Intermediate mediate Amine [M + 1]⁺ (min) Method 100

2a [1,4′]- Bipiper- idinyl-3-ol Biphenyl- 3-yl- methan- amine 486 1.53 2C 101

2a [1,4′]Bi- piperidinyl- 4-ol Biphenyl- 4-yl- methan- amine 486 1.51 2C 102

2a [1,4′]Bi- piperidinyl- 4-ol Biphenyl- 3-yl- methan- amine 486 1.52 2C 103

6-chloro- pyrimidine-4- carbonyl chloride [1,4′]- Bipiperidin- in-yl-3-ol Biphenyl- 4-yl- methan- amine 472 1.59 2C

Example 104

Intermediate 25i (17 mg, 0.05 mmol), 3-fluoro-4-methyl-benzylamine (10 mg, 0.075 mmol) and diisopropyl-ethyl amine (0.013 ml, 0.075 mmol) in 1 ml of dry DMSO were stirred at 80° C. overnight. The reaction mixture was concentrated under vacuum. The crude product was purified by reverse phase preparative HPLC. 20 mg (0.047 mmol) of the desired product were obtained.

HPLC (Method C): R_(t). (min)=1.45

[M+H]⁺=426

The following examples were synthesized in analogy to the preparation of Example 104.

HPLC Ex Inter- Rt_(•) # STRUCTURE mediate Amine [M + H]⁺ (min) Method 105

25f 2-(3- chloro-4- methoxy- phenyl)- ethyl- amine 488 1.43 2C 106

25f 2-(4- isopropyl- phenyl)- ethylamine 466 2.88 2B 107

25h 3,4- dichloro- benzyl- amine 464 5.6 1A 108

25f Cyclohexyl- methan- amine 416 2.67 2B 109

25f 3,4- dichloro- benzyl- amine 478 2.81 2B 110

25f 4-chloro- benzyl- amine 444 1.6 2A 111

25f 3-chloro-4- fluoro- benzyl- amine 462 1.63 2A 112

25f 2-(4-tert- butyl- phenyl)- ethylamine 480 1.8 2A 113

25f (1-phenyl- piperidin- 4- yl)methan- amine 493 1.32 2A 114

25f 7a 492 7.42 2F 115

25f 2-(3,4- difluoro- phenyl)- ethylamine 460 1.61 2A 116

25f 3-chloro- 4-tri- fluoro- methyl- benzyl- amine 512 1.74 2A 117

25f 4-chloro-3- fluoro- benzyl- amine 462 1.64 2A 118

25f 4-fluoro-3- methyl- benzyl- amine 442 1.61 2A 119

25f 243- chloro-4- methoxy- phenyl)- ethyl- amine 488 1.63 2A 120

25f 3-fluoro-4- methyl- benzyl- amine 442 1.61 2A 121

25f (4- phenylcyclo- hexyl)- methan- amine 492 1.78 2A 122

25f 2-(3-chloro- phenyl)- ethylamine 458 1.63 2A 123

25f 3-chloro- benzyl- amine 444 1.6 2A 124

25f 2-(4-chloro- phenyl)- ethylamine 458 1.65 2A 125

25f 4-chloro-3- trifluoro- methyl- benzyl- amine 512 1.74 2A 126

25f 2-(3,4- dimethyl- phenyl)- ethylamine 452 1.68 2A 127

25i 4-chloro- benzyl- amine 428 1.65 2A 128

25i 3-chloro-4- fluoro- benzyl- amine 446 1.67 2A 129

25i 2-(4-tert- butyl- phenyl)- ethylamine 464 1.84 2A 130

25i (1-phenyl- piperidin- 4-yl)- methen- amine 477 1.37 2A 131

25i 7a 476 1.84 2A 132

25i 2-(3,4- difluoro- phenyl)- ethylamine 444 1.66 2A 133

25i 3-chloro-4- trifluoro- methyl- benzyl- amine 496 1.79 2A 134

25i 4-chloro-3- fluoro- benzyl- amine 446 1.67 2A 135

25i 4-fluoro-3- methyl- benzyl- amine 426 1.65 2A 136

25i 2-(3- chloro-4- methoxy- phenyl)- ethylamine 472 1.66 2A 137

25i 3-fluoro-4- methyl- benzyl- amine 426 1.65 2A 138

25i (4- phenylcyclo- hexyl)- methan- amine 476 1.84 2A 139

25i 2-(3- chloro- phenyl)- ethylamine 442 1.68 2A 140

25i 3-chloro- benzyl- amine 428 1.64 2A 141

25i 2-(4- chloro- phenyl)- ethylamine 442 1.69 2A 142

25i 4-chloro-3- trifluoro- methyl- benzyl- amine 496 1.79 2A 143

25i 2-(3,4- dimethyl- phenyl)- ethylamine 436 1.72 2A 144

25f 7a 492 7.7 2H (iso- cratic) 145

25f 7a 492 10.2 2H (iso- cratic)

Example 146

Intermediate 25b (80 mg, 0.18 mmol), Intermediate 7c (40 mg, 0.21 mmol) and N,N-diisopropyl-ethyl amine (0.046 ml, 0.26 mmol) in 0.2 ml of dry 1,4-dioxane were mixed in a microwave vial and reacted in the following conditions: Power 100, Ramp 5 min, Hold 2 h, Temperature 150° C., Pression 150° C., Stirring. The reaction mixture was concentrated under vacuum and diluted with dichloromethane. The organic phase was washed with an aqueous saturated sodium bicarbonate solution, dried over sodium sulfate and concentrated under vacuum. The crude product was purified by reverse phase preparative HPLC. 36 mg (0.06 mmol) of the desired product were obtained.

HPLC (Method 1E Hydro): R_(t). (min)=9.52

[M+H]⁺=583

The following examples were synthesized in analogy to the preparation of Example 146

HPLC Ex R_(t•) # STRUCTURE Intermediate Amine [M + H]⁺ (min) Method 147

25c (trans-2- phenyl- cyclo- propyl)- methan- amine 555 8.48 1E (Hydro) 148

25b (1,2,3,4- tetrahydro- naphthalen- 1-yl)- methan- amine 555 8.62 1E (Hydro) 149

25b 9c 570 8.7 1E (Hydro) 150

25b 7d 583 9.12 1E (Hydro) 151

25b 7e 583 9.22 1E (Hydro) 152

25b (trans-2- phenyl- cyclo- propyl)- methan- amine 541 8.03 1E (Hydro) 153

25b 2-(4-tert- butyl- phenyl)- ethyl- amine 571 9.42 1E (Hydro) 154

25b 11 643 8.65 1E (Hydro) 155

25b 9a 584 8.52 1E (Hydro) 156

25b 9b 570 8.48 1E (Hydro) 157

25b Quinolin- 3- ylmethan- amine 552 1.28 2F 158

25b 7b 583 9.48 1E (Hydro) 159

25l 9b 584 8.85 1E (Hydro) 159a

25n 7a 613 2.21 2Ca 159b

25n 4-tert- butyl- benzyl- amine 587 1.89 2Ca 159c

25b 7m 603 9.88 1E (Hydro) 159d

25b 7l 569 9.62 1E (Hydro) 159e

25b C- Cyclohexyl- methyl- amine 507 8.37 1E (Hydro) 159f

25b C-(4- isopropyl- cyclo- hexyl)- methyl- amine 549 10.12 1E (Hydro) 159g

25b C-(3- methyl- cyclo- hexyl)- methyl- amine 521 9.25 1E (Hydro) 159h

25b C-(3,3- dimethyl- cyclo- hexyl)- methyl- amine 535 9.68 1E (Hydro) 159i

25d 7a 533 9.53 1E (Hydro) 159k

25b C-(4- ethyl- cyclo- hexyl)- methyl- amine 535 9.98 1E (Hydro) 159l

25b C-(4- methyl- cyclo- hexyl)- methyl- amine 521 9.28 1E (Hydro) 159m

25a 7a 569 9.33 1E (Hydro) 159n

25b C-(3- pyridin- 2yl-cyclo- hexyl)- methyl- amine 584 7.90 8.05 1E (Hydro) 159o

25b C-(4-tert- butyl- cyclo- hexyl)- methyl- amine 563 10.87 1E (Hydro) 159p

25d 7c 533 9.53 1E (Hydro) 159q

25b 7n 587 9.37 1E (Hydro) 159r

25b C-[4-(1H- Benzo- imidazol- 2-yl)- cyclo- hexyl]- methyl- amine 623 7.17 1E (Hydro) 159s

25b C-[(4- phenyl- morpholin- 2-yl)- methyl- amine 586 7.73 1E (Hydro) 159t

25b C-(1- pheny- cyclo- hexyl)- methyl- amine 583 9.5 1E (Hydro) 159u

25b C-(5- pheny- furan-2yl)- methyl- amine 567 8.93 1E (Hydro) 159w

25b 9d 652 9.57 1E (Hydro) 159y

25b 2-(1- methyl- 1H-indol- 3yl)-ethyl- amine 568 8.2 1E (Hydro) 159x

25b C-Indan- 1-yl- methyl- amine 541 8.27 1E (Hydro) 159z

25b 7g 601 9.8 1E (Hydro) 159aa

25d 7g 551 9.47 1E (Hydro) 159ba

25a 7g 587 9.32 1E (Hydro) 159ca

25a 7f 603 9.95 1E (Hydro) 159da

25b 7f 617 10.5 1E (Hydro) 159ea

25d 7f 567 7.4 2F 159fa

25b C-cyclo- heptyl- methyl- amine 521 8.88 1E (Hydro) 159ga

25l 54a 653 5.38 2M 159ha

25b 54a 639 5.94 2M 159ia

25b 54b 585 5.42 2M 159ja

25l 54b 599 4.76 2M 159ka

25l 55g 653 9.37 1E (Hydro) 159la

25b 55g 639 9.02 1E (Hydro) 159ma

25b 54g 639 9.07 1E (Hydro) 159na

25b 53e 603 8.6 1E (Hydro) 159oa

25l 53c 599 9.01 1E (Hydro) 159pa

25b 53a 639 8.38 1E (Hydro) 159qa

25l 53a 653 8.85 1E (Hydro) 159ra

25b 53b 585 7.86 1E (Hydro) 159sa

25l 53b 599 8.36 1E (Hydro) 159ta

25l 53e 617 9.03 1E (Hydro) 159ua

25l 54f 619 8.63 1E (Hydro) 159wa

25b 54f 605 8.10 1E (Hydro) 159ya

25l 54d 617 5.08 2M 159xa

25b 7h 613 9.95 1E (Hydro) 159za

25b 7i 597 10.52 1E (Hydro) 159ab

25b 53f 605 9.0 1E (Hydro) 159bb

25b C-(3- methyl- cyclo- pentyl)- methyl- amine 507 8.53 1E (Hydro) 159cb

25b 53c 585 8.77 1E (Hydro) 159db

25b 7j 601 10 1E (Hydro) 159eb

25b 53h 571 7.93 1E (Hydro) 159fb

25b C-(5- phenyl- tetrahydro- furan-3yl)- methyl- amine 571 7.83 1E (Hydro) 159gb

25b 54c 585 8.36 1E (Hydro) 159hb

25b 53g 639 8.94 1E (Hydro) 159ib

25l 53g 653 9.27 1E (Hydro) 159jb

25b 55c 585 8.38 1E (Hydro) 159kb

25g 7g 524 2.87 1Fa 159lb

25g 7f 540 3.02 1Fa 159mb

25b 7r 567 8.85 1E (Hydro) 159nb

25b C- Bicyclo[4. 2.0]octa- 1(6),2,4- trien-7-yl- methyl- amine 527 7.53 1E (Hydro) 159ob

25b C- Chroman- 2yl- methyl- amine 557 7.9 1E (Hydro) 159pb

25b C-(1,2,3,4- Tetra- hydro- naphthalen- 2-yl-)- methyl- amine 555 8.47 1E (Hydro) 159qb

25b C-(2,3- Dihydro- benzo- furan-2yl)- methyl- amine 543 7.4 1E (Hydro) 159rb

25b C-(5- Chloro- 2,3- Dihydro- benzo- furan-2yl)- methyl- amine 557 6.5 2F 159sb

25b C-(6- Chloro- croman-3- yl)- methyl- amine 591 8.09 1E (Hydro) 159tb

25b 7s 589 9.8 1E (Hydro) 159ub

25b 7t 555 9.07 1E (Hydro) 159wb

25b 7u 589 9.7 1E (Hydro) 159yb

25b 7v 555 9.02 1E (Hydro) 159xb

25b 7o 587 9.55 1E (Hydro) 159zb

25b 7k 549 10.37 1E (Hydro) 159ac

25b C-(tetra- hydro- pyran-4- yl)- methyl- amine 509 5.92 1E (Hydro) 159bc

25b C-(tetra- hydro- pyran-3- yl)- methyl- amine 509 6.15 1E (Hydro) 159cc

25l 7o 601 5.40 2M 159dc

25o C- cyclohexyl- methyl- amine 446 1.23 2Gb 159ec

25o Indan-2- yl-amine 466 1.24 2Gb 159fc

25o C-Indan- 2-yl- methyl- amine 480 2.97 2Ga 159gc

25b C-(1,2,3,4- Tetra- hydro- quinolin- 2-yl)- methyl- amine 556 1.35 2Ca

Example 160

Intermediate 28b (80 mg, 0.20 mmol), Intermediate 13 (74 mg, 0.30 mmol) and N,N-diisopropyl-ethylamine (0.087 ml, 0.51 mmol) in 2 ml of dichloromethane were stirred at room temperature for 10 min Sodium triacetoxyborohydride (129 mg, 0.61 mmol) was added and the reaction mixture was stirred at room temperature overnight. The organic phase was washed with an aqueous saturated sodium bicarbonate solution, dried over sodium sulfate and concentrated under vacuum. The crude product was purified by reverse phase preparative HPLC. 39 mg (0.06 mmol) of the desired product were obtained.

HPLC (Method 2F): R_(t). (min)=7.25

[M+H]⁺=583

The following examples were synthesized in analogy to the preparation of Example 160.

HPLC Ex Inter- Amine or R_(t•) # STRUCTURE mediate Ketone [M + H]⁺ (min) Method 161

28f N-Methyl- N- piperidin- 4-yl- methane- sulfon- amide 571 7.17 2F 162

28f Morpho- line 466 9.97- 10.27 1E 163

28f Pyrroli- dine 450 7.06 2F 164

28a 4,4- difluoro- piperidine 512 8.17 1E 165

28a (R)- pyrrolidin- 3-ol 478 7.62 1E 166

28a (S)- pyrrolidin- 3-ol 478 7.57 1E 167

28a 4-fluoro- piperidine 494 7.37 2F 168

28a N- piperidin- 4yl- methan- sulfon- amide 569 7.28 1E (Fusion) 169

28a (S)-N- piperidin- 3yl- methan- sulfon- amide 569 8.50 1E 170

28a N- piperidin- 4yl- isobutyr- amide 561 7.58 1E 171

28a N- piperidin- 4yl- acetamide 533 7.07 2F 172

28a Piperidin- 4- carboxylic acid amide 519 7.07 1E (Fusion) 173

28a Piperidin- 4- carboxylic acid methyl- amide 533 7.73 1E (Fusion) 174

28a (R)-N- piperidin- 3yl- methan- sulfon- amide 569 8.48 1E (Fusion) 175

28a (S)- piperidine- 3- carboxylic acid amide 519 8.70 1E (Fusion) 176

28a (S)- piperidine- 3- carboxylic acid methyl amide 533 7.03 2F 177

28a (S)- piperidine- 3- carboxylic acid dimethyl amide 547 7.15 2F 178

28a N-Ethyl- N- piperidin- 4-yl- methane- sulfon- amide 597 9.62 1E (Hydro) 179

28a (S)- piperidine- 3- carboxylic acid 520 6.60 1E (Fusion) 180

28b Methyl-(3- methyl- oxetan- 3yl- methyl)- amine 492 8.05 1E (Hydro) 181

28b 2- (methoxy- ethyl)- methyl- amine 466 7.72 1E (Hydro) 182

28b Methyl- amino- aceto- nitrile 447 8.00 1E (Hydro) 183

28b 2,3- dihyro- 1H- isoindole 496 9.52 1E (Hydro) 184

28b 4-trifluoro- methyl- piperidine 530 9.60 1E (Hydro) 185

28b 18 585 7.33 1E (Hydro) 186

28b Piperidin- 4- carboxylic acid methyl- amide 519 7.42 1E (Hydro) 187

28b Piperidin- 4yl-urea 520 7.05 2F 188

28b 2- methansul- fonyl-2,8- diaza- spiro[4.5]- decane 595 8.32 1E (Hydro) 189

28b 4-(1,1- dioxo-iso- thiazolidin- 2-yl)- piperidine 581 8.23 1E (Hydro) 190

28b 2,8- diazaspiro [4.5]decan- 1-one 531 7.58 1E (Hydro) 191

28b 16a 585 7.65 1E (Hydro) 192

28b 1-piperidin- 4-yl- pyrrolidin- 2-one 545 8.08 1E (Hydro) 193

28b Azetidin- 3- carboxylic acid methyl- amide 491 7.55 1E (Hydro) 194

28b N-methyl- N- piperidin- 4yl- acetamide 533 7.87 1E (Hydro) 195

28b Ethan- sulfonic acid- piperidin- 4-yl-amide 569 8.15 1E (Hydro) 196

28c Piperidine- 4-sulfonic acid dimethyl- amide 557 9.11 1E (Hydro) 197

28b Propan-2- sulfonic acid- piperidin- 4-yl-amide 583 8.37 1E (Hydro) 198

28c 4-ethoxy- piperidine 494 10.75 1E (Hydro) 199

28c N- piperidin- 4-methyl- methan- sulfon- amide 557 9.45 1E (Hydro) 200

28c 4-tert- butyl- piperidine 506 7.86 2F 201

28c 4- (piperidin- 4-yl)- pyridine 527 10.88 1E (Hydro) 202

28c Piperidine- 4-carbo- nitrile 475 9.77 1E (Hydro) 203

28c 4-(3,4- difluoro- phenoxy)- piperidine 578 11.05 1E (Hydro) 204

28c 2- (piperidin- 4-yloxy)- pyridine 543 10.38 1E (Hydro) 205

28c Propan-2- sulfonic- acid- piperidin- 4-yl-amide 571 9.12 1E (Hydro) 206

28 N-Ethyl- N- piperidin- 4-yl- methane- sulfon- amide 571 10.18 1E (Hydro) 207

28g Piperidine- 4-sulfonic acid dimethyl- amide 571 9.67 1E (Hydro) 208

28c 4- methoxy- piperidine 480 2.21 2G 209

28c 2-methyl- morpho- line 466 3.46 2F 210

28c 3-Phenyl- pyrroli- dine 512 9.68 2F 211

28c Piperidin- 4- carboxylic acid sec- butyl amide 549 9.53 1E (Hydro) 212

28c 4-(3,5- dimethyl- [1,2,4]- triazol-4- yl)- piperidine 545 8.93 1E (Hydro) 213

28c 4-(3- methyl- [1,2,4]- oxadiazol- 5-yl)- piperidine 532 8.21 2F 214

28c N-methyl- 2-(R)- (pyrrolidin- 2-yl) acetamide 507 9.35 1E (Hydro) 215

28c N-methyl- 2-(S)- (pyrrolidin- 2-yl) acetamide 507 9.24 1E (Hydro) 216

28c N,N- dimethyl- 2-(R)- (pyrrolidin- 2-yl) acetamide 521 9.71 1E (Hydro) 217

28c N,N- dimethyl- 2-(S)- (pyrrolidin- 2-yl) acetamide 521 9.72 1E (Hydro) 218

28c 2,6- dimethyl- morpho- line 480 8.92 2F 219

28c (R)-3- methoxy- pyrroli- dine 466 7.23 2F 220

28c (S)-3- methoxy- pyrroli- dine 466 7.23 2F 221

28c Piperidine- 4-sulfonic acid methyl- amide 543 8.50 1E (Hydro) 222

28c N- azetidin-3- yl-N- methyl- methane- sulfon- amide 529 8.65 1E (Hydro) 223

28c N- azetidin-3- yl- methane- sulfon- amide 515 8.02 1E (Hydro) 224

28c 4-methyl- piperidine- 4- carboxylic acid methyl- amide 521 9.00 1E (Hydro) 225

28c 4-phenyl- piperidine 526 10.83 1E (Hydro) 226

28b N-methyl- N-(S)- (pyrrolidin- 3yl)- methane- sulfon- amide 555 8.04 1E (Hydro) 227

28b 16b 599 8.13 1E (Hydro) 228

28b Piperidine- 4-sulfonic acid amide 541 7.12 1E (Hydro) 228a

28c Methyl- (tetra- hydro- pyran-3- yl)-amine 480 10,05 1E (Hydro) 228b

41b 3- methoxy- tetrahydro- pyran-4- one 522 9,25 1E (Hydro) 228c

41a 3- methoxy- tetrahydro- pyran-4- one 496 8,87 1E (Hydro) 228d

41a 3-fluoro- tetrahydro- pyran-4- one 484 1E (Hydro) 228e

41a N-carb- ethoxy-3- methoxy- 4- piperidone 567 7,42 2F 228f

41a 4- chromanone 514 10,31 1E (Hydro) 228g

41a 43 530 9,76 1E (Hydro) 228ga

28c 47a 496 5.77 2M 228gb

28c 1-(2- Methoxy- ethyl)- 3a,4,5,6,7, 7a- hexahydro- 1H- pyrazolo- [3,4- c]pyridine 546 9.55 1E (Hydro) 228gc

28c 1-((R)-3- Amino- piperidin- 1-yl)- ethanone 507 8.85 1E (Hydro) 228gd

28c (R)-1- Methane- sulfonyl- piperidin- 3-yllamine 543 9.11 1E (Hydro) 228ge

28c 3- Phenoxy- methyl- pyrrolidine 542 10.92 1E (Hydro) 228gf

28c 3- Pyrrolidin- 3-yl- pyridine 527 10.00 1E (Hydro) 228gg

28c 3- Trifluoro- methyl- 5,6,7,8- tetrahydro- [1,6]naph- thyridine 567 7.69 2F 228gh

28 C- (Tetrahydro- pyran-2- yl)methyl- amine 480 2.09 2Cb 228gi

28c 56 515 2.18 2Cb 228gj

28c 1-Oxa-3,8- diaza- spiro[4,5] decan-2- one 521 8.30 1E (Hydro) 228gk

28c 4- Piperidin- 4-yl- benzonitrile 551 10.35 1E (Hydro) 228gl

28c 4-(3,4- Difluoro- benzyl)- piperidine 576 11.42 1E (Hydro) 228gm

28c 8-Aza- bicyclo[3. 2.1]octan- 3-ol 492 9.30 1E (Hydro) 228gn

28c 45 496 5.96 2M 228go

41a 3- Methoxy- tetrahydro- pyran-4- one 508 5.77 2M 228gp

41a 3- Tetrazol- 2-yl- tetrahydro- pyran-4- one 534 7.09 2F

Example 228h

Example 228b (22 mg, 0.032 mmol), formaldehyde (0.003 ml, 0.096 mmol), N,N-diisopropyl-ethylamine (0.008 ml, 0.048 mmol) and trifluoroacetic acid (0.005 ml) in 1.5 ml of methanol were stirred at room temperature for 5 min. Sodium cyanoborohydride (10 mg, 0.160 mmol) was added and the reaction mixture was stirred at room temperature overnight. The organic phase was concentrated under vacuum. The crude product was purified by flash chromatography (Isolute silica gel cartridge 5 g, eluent: ethyl acetate/methanol=7:3%). 8.4 mg (0.016 mmol) of the desired product were obtained.

The following examples were synthesized in analogy to the preparation of Example 228h.

HPLC Ex Starting R_(t•) # STRUCTURE example [M + H]⁺ (min) Method 228 ha

228ga 510 5.72 2M

Example 229

Intermediate 28a (100 mg, 0.25 mmol), (S)-3-hydroxypiperidine (67 mg, 0.49 mmol) and trimethylorthoformate (1.07 ml, 9.82 mmol) in 5 ml of methanol were stirred at 60° C. for 1 h. 2-picoline borane complex (26 mg, 0.25 mmol) was added and the reaction mixture was stirred at 60° C. overnight. The reaction mixture was concentrated under vacuum. The crude product was purified by reverse phase preparative HPLC. 64 mg (0.13 mmol) of the desired product were obtained.

HPLC (Method 1E): R_(t). (min)=7.18

[M+H]⁺=492

The following examples were synthesized in analogy to the preparation of Example 229.

HPLC Ex Inter- R_(t•) # STRUCTURE mediate Amine [M + H]⁺ (min) Method 230

28a 1- piperazin- 1-yl- ethanone 519 7.13 2F 231

28a (R)- piperidin- 3-ol 492 7.35 1E (Fusion) 232

28a (R)- pyrrolidin- 3- carboxylic acid amide 505 7.83 1E (Fusion) 233

28b 3-fluoro- piperidine 480 8.32 1E (Hydro)

Example 234

Intermediate 28d (20 mg, 0.05 mmol), 2-methyl-morpholine (0.012 ml, 0.10 mmol), sodium triacetoxyborohydride (43 mg, 0.20 mmol), acetic acid (0.05 ml) and trimethylorthoformate (0.05 ml) in 0.9 ml of DMA were stirred at room temperature for 3 h. The reaction mixture was concentrated under vacuum. The crude product was purified by reverse phase preparative HPLC. 3 mg (0.006 mmol) of the desired product were obtained.

HPLC (Method A): R_(t). (min)=1.74

[M+H]⁺=486

The following examples were synthesized in analogy to the preparation of Example 234.

HPLC Ex Inter- [M + R_(t•) Meth- # STRUCTURE mediate Amine H]⁺ (min) od 235

28b Azepane 476 1.72 2A 236

28d Dimethyl- piperidin- 4yl-amine 513 1.64 2A 237

28a 2-methyl- morpho- line 492 1.72 2A 238

28b Pyrrolidin- 3-ol 464 1.65 2A 239

28d Pyrrolidin- 3-ol 472 1.71 2A 240

28a 2-phenyl- morpho- line 554 1.84 2A 241

28a Pyrrolidin- 3-ol 478 1.68 2A 242

28b [1,4]- oxazepane 478 1.66 2A 243

28d [1,4]- oxazepane 486 1.72 2A 244

28b 4,4- difluoro- piperidine 498 1.72 2A 245

28b Azepan- 4-ol 492 1.65 2A 246

28a (3S,4R)- piperidine- 3,4-diol 508 1.66 2A 247

28a Azepan- 4-o1 506 1.68 2A

Example 248

Intermediate 27e (105 mg, 0.33 mmol), TBTU (215 mg, 0.67 mmol) and N,N-diisopropyl-ethylamine (0.12 ml, 0.67 mmol) in 2 ml DMF were stirred at room temperature for 5 min Intermediate 20f (100 mg, 0.33 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under vacuum and the crude product was dissolved in dichloromethane. The organic phase was washed with an aqueous saturated sodium bicarbonate solution, dried over sodium sulfate and concentrated under vacuum. The crude product was purified by flash chromatography (Si Isolute cartridge (5 g); eluent: ethyl acetate/methanol=90/10%). 30 mg (0.057 mmol) of the desired product were obtained.

HPLC (Method 1E Hydro): R_(t). (min)=9.2

[M+H]⁺=521

The following examples were synthesized in analogy to the preparation of Example 248.

Inter- HPLC Ex me- [M + R_(t•) Meth- # STRUCTURE diate Amine H]⁺ (min) od 249

27i 20a 568 10.07 1E (Hy- dro) 250

27c 1- pyrrolidin- 3-yl- piper- idine 436 1.5 1E (Hy- dro) 251

27c [1,3′]- Bipyrro- lidinyl 422 10.35 1E (Hy- dro) 252

27a [1,4′]- Bipiper- idinyl- 4′ car- boxylic- acid amide 519 8.60 1E (Fu- sion) 253

27a 4- pyrroli- din-1yl- piper- idine 462 7.07 2F 254

27b 20g 555 7.50 1E (Hy- dro) 255

27b 20a 569 8.15 1E (Hy- dro) 256

27b 20j 491 7.03 1E (Hy- dro) 257

27b 20i 505 7.43 1E (Hy- dro) 258

27b 20d 541 7.50 1E (Hy- dro) 259

27b 20c 541 7.48 1E (Hy- dro) 260

27b 20h 505 7.85 1E (Hy- dro) 261

27c 20f 507 8.70 1E (Hy- dro) 262

27e 20g 557 9.11 1E (Hy- dro) 263

27c 20m 587 8.79 2F 264

27c 20e 557 8.85 1E (Hy- dro) 265

27c 20l 479 8.37 1E (Hy- dro) 266

27e 20f 521 9.2 1E (Hy- dro) 267

27e 20l 493 8.93 1E (Hy- dro) 268

39b 20a 542 3.54 2F 269

39b 4- piper- idin- 4-yl- morpho- line 436 7.43 2F 270

39a 20a 553 8.28 2F 271

39a 4- piper- idin- 4-yl- morpho- line 449 7.60 2F 272

39c 20a 556 7.98 2F 273

39c 4- piper- idin- 4-yl- morpho- line 450 7.29 2F 274

39d 24 554 8.28 1E (Hy- dro) 275

39d [1,4′]- bipiper- idinyl- 4-ol 477 777 1E (Hy- dro) 275a

27c 20la 480 10.03 1E (Hy- dro) 275b

27c 20lb 510 9.48 1E (Hy- dro) 275c

27c 20lb 508 10.27 1E (Hy- dro) 275d

27c 20ld 514 10.13 1E (Hy- dro) 275da

27hc 20lg 526 9.16 1E (Hy- dro) 275db

27hd 20lg 526 9.18 1E (Hy- dro) 275dc

27hs 20lg 508 7.25 1F 275dd

27hf 20lf 494 6.53 2F 275de

27hr 20lg 508 8.55 1E (Hy- dro) 275df

27he 20lg 494 8.07 1E (Hy- dro) 275dg

27hf 20lg 494 8.10 1E (Hy- dro) 275dh

27ha 20lf 522 9.03 1E (Hy- dro) 275di

27ha 20lg 522 9.00 1E (Hy- dro) 275dj

27ha 20la 536 9.76 1E (Hy- dro) 275dk

27ib 20a 595 2.16 2Cb 275dl

27ic 20a 593 2.20 2Cb

Example 276

Intermediate 27g (50 mg, 0.14 mmol), HATU (55 mg, 0.14 mmol) and N,N-diisopropyl-ethylamine (0.05 ml, 0.28 mmol) in 2 ml DMF were stirred at room temperature for 5 min 4-piperidin-4-yl-morpholine (24 mg, 0.14 mmol) was added and the reaction mixture was stirred at room temperature 3 h. The reaction mixture was concentrated under vacuum and the crude product was dissolved in dichloromethane. The organic phase was washed with an aqueous saturated sodium bicarbonate solution, dried over sodium sulfate and concentrated under vacuum. The crude product was purified by reverse phase preparative HPLC. 80 mg (0.13 mmol) of the desired product were obtained.

HPLC (Method C): R_(t). (min)=1.57

[M+H]⁺=486

The following examples were synthesized in analogy to the preparation of Example 276.

HPLC Ex Inter- R_(t•) # STRUCTURE mediate Amine [M + H]+ (min) Method 277

27h 4-piperidin- 4-yl- morpholine 536 1.69 2C 278

27h [1,4′]- Bipiperidinyl- 4-ol 550 1.65 2C 279

27a 4-piperidin- 4-yl- morpholine 478 1.52 2C 280

27f [1,4′]- Bipiperidinyl- 4-ol 506 1.52 2C 281

27f 4-piperidin- 4-yl- morpholine 492 1.53 2C 282

27g [1,4′]- Bipiperidinyl- 4-ol 500 1.55 2C 283

39e [1,4′]- Bipiperidinyl- 4-ol 484 1.66 2C

Example 284

Intermediate 30 (45 mg, 0.088 mmol) and N,N-diisopropylethylamine (0.05 ml, 0.27 mmol were dissolved in 5 ml of dichloromethane. The reaction mixture was stirred at 0° C. and isobutyrylchloride (0.01 ml, 0.09 mmol) was added. The reaction mixture was stirred at 0° C. for 20 min, then it was washed with an aqueous saturated sodium bicarbonate solution, dried over sodium sulfate and concentrated under vacuum. The crude product was suspended and stirred in diisopropyl ether, the solid filtered off to obtain 30 mg (0.05 mmol) of the desired compound.

HPLC (Method 1E): R_(t). (min)=7.02

[M+H]⁺=547

The following examples were synthesized in analogy to the preparation of Example 284.

HPLC Ex Inter- R_(t•) # STRUCTURE mediate Chloride [M + H]⁺ (min) Method 285

30 Methane- sulfonyl chloride 555 6.91 2F

Example 286

Intermediate 32 (100 mg, 0.26 mmol) and cyclopentanone (0.02 ml, 0.26 mmol) in 2 ml of dichloromethane were stirred at room temperature for 10 min Sodium triacetoxyborohydride (132 mg, 0.62 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with an aqueous saturated sodium bicarbonate solution, dried over sodium sulfate and concentrated under vacuum. The crude product was purified by reverse phase preparative HPLC. 31 mg (0.07 mmol) of the desired product were obtained.

HPLC (Method 2F): R_(t). (min)=7.52

[M+H]⁺=450

The following examples were synthesized in analogy to the preparation of Example 286.

HPLC Ex Inter- R_(t•) # STRUCTURE mediate Ketone [M + H]⁺ (min) Method 287

32 Acetone 424 7.24 2F 288

33 Tetrahydro- pyran-4-one 466 7.18 2F

Example 289

Intermediate 25b (200 mg, 0.46 mmol) 4-tert-butylphenylboronic acid (99 mg, 0.56 mmol), tetrakis(triphenylphosphine)palladium (53 mg, 0.05 mmol) and 0.56 ml of a 2M aqueous solution of sodium carbonate in 2 ml of 1,2-dimethoxyethane were stirred at 80° C. overnight. After cooling to room temperature, water was added and the reaction mixture was extracted with dichloromethane. The organic phase was washed with an aqueous saturated sodium bicarbonate solution, dried over sodium sulfate and concentrated under vacuum. The crude product was purified by flash chromatography (Si Isolute cartridge (5 g); eluent: ethyl acetate/methanol=95/5%). 41 mg (0.08 mmol) of the desired product were obtained.

HPLC (Method 1E Hydro): R_(t). (min)=9.93

[M+H]⁺=528

Example 290

Intermediate 25b (60 mg, 0.14 mmol) and 4-chlorophenol (0.014 ml, 0.14 mmol) were dissolved in 2 ml of DMF. Cesium carbonate (45 mg, 0.14 mmol) was added and the reaction mixture was stirred at room temperature overnight. The solvent was concentrated under vacuum, the crude product was dissolved in dichloromethane and the organic phase was washed with water, dried over sodium sulfate and concentrated under vacuum. The crude product was purified by flash chromatography (Si Isolute cartridge (5 g); eluent: dichloromethane/ethyl acetate=90/1%). 50 mg (0.09 mmol) of the desired product were obtained.

HPLC (Method 1E Hydro): R_(t). (min)=8.9

[M+H]⁺=522

The following example was synthesized in analogy to the preparation of Example 290.

HPLC Ex Inter- R_(t•) # STRUCTURE mediate Phenol [M + H]⁺ (min) Method 291

25b 4- tertbutyl- phcnol 544 7.64 2F

Example 292

Sodium hydride (19 mg, 0.46 mmol) and 4-chloro-3-methylbenzylalcohol (44 mg, 0.28 mmol) were suspended in 5 ml of dry tetrahydrofuran. The reaction mixture was stirred at room temperature for 10 min, then Intermediate 25b (100 mg, 0.23 mmol) was added. The reaction mixture was stirred at 50° C. overnight. The solvent was concentrated under vacuum, the crude product was dissolved in dichloromethane and the organic phase was washed with water, dried over sodium sulfate and concentrated under vacuum. The crude product was purified by flash chromatography (Si Isolute cartridge (5 g); eluent: dichloromethane/methanol=95/5%). 40 mg (0.07 mmol) of the desired product were obtained.

HPLC (Method 1E Hydro): R_(t). (min)=9.95

[M+H]⁺=550

The following examples were synthesized in analogy to the preparation of Example 292.

HPLC Ex Inter- [M + R_(t•) Meth- # STRUCTURE mediate Phenol H]⁺ (min) od 293

25b 4- hydroxy- methyl- benzo- nitrile 527 8.17 1E (Hy- dro) 294

25b (3-fluoro- 4- methyl- phenyl)- methanol 534 9.12 1E (Hy- dro) 295

25b (1-phenyl- pyrrolydin- 3-yl)- methanol 571 10.2 1E (Hy- dro) 296

25b (4-tert- butyl- phenyl)- methanol 558 2.71 1F 297

25f (4-tert- butyl- phenyl)- methanol 466 9.50 1E (Hy- dro) 298

25h (4-tert- butyl- phenyl)- methanol 453 8.01 2F 299

25a (4-tert- butyl- phenyl)- methanol 544 9.68 1E (Hy- dro) 300

25d (4-tert- butyl- phenyl)- methanol 508 10.25 1E (Hy- dro) 301

25n (4-tert- butyl- phenyl)- methanol 588 2.20 2Ca 302

25n (3-Phenyl- cyclo- hexyl)- methanol 614 2.18 2Ca 

1. A process for the production of a compound of formula (I),

wherein R₁ is selected from among

R₂ is selected from among —H, -halogen, —CN, —O—C₁-C₄-alkyl, —C₁-C₄-alkyl, —CH═CH₂, —C≡CH, —CF₃, —OCF₃, —OCF₂H, and —OCFH₂; R₃ is selected from among —H, -methyl, -ethyl, -propyl, -i-propyl, -cyclopropyl, —OCH₃, and —CN; R₄ and R₅ are independently selected from among an electron pair, —H, and a group selected from among —C₁-C₆-alkyl, —NH₂, —C₃-C₈-cycloalkyl, —C₃-C₈-heterocyclyl, —C₅-C₁₀-aryl, —C₅-C₁₀-heteroaryl, and —C(O)—N(R₈,R_(8′)), with R₈ and R_(8′) independently being selected from among —H, and —C₁-C₆-alkyl, and wherein R₄ and R₅ if different from an electron pair or —H are optionally independently substituted with one or more groups selected from among -halogen, —OH, —CF₃, —CN, —C₁-C₆-alkyl, —O—C₁-C₆-alkyl, —O—C₃-C₈-cycloalkyl, —O—C₃-C₈-heterocyclyl, —O—C₅-C₁₀-aryl, —O—C₅-C₁₀-heteroaryl, —C₀-C₆-alkylene-CN, —C₀-C₄-alkylene-O—C₁-C₄-alkyl, —C₀-C₄-alkylene-O—C₃-C₈-cycloalkyl, —C₀-C₄-alkylene-O—C₃-C₈-heterocyclyl, —C₀-C₄-alkylene-O—C₅-C₁₀-aryl, —C₀-C₄-alkylene-O—C₅-C₁₀-heteroaryl, —C₀-C₄-alkylene-Q-C₀-C₄-alkyl-N(R₉,R_(9′)), —C₀-C₄-alkylene-N(R₁₀))-Q-C₁-C₄-alkyl, —C₀-C₄-alkylene-N(R₁₀)-Q-C₃-C₈-cycloalkyl, —C₀-C₄-alkylene-N(R₁₀)-Q-C₃-C₈-heterocyclyl, —C₀-C₄-alkylene-N(R_(a)))-Q-C₅-C₁₀-aryl, —C₀-C₄-alkylene-N(R_(a)))-Q-C₅-C₁₀-heteroaryl, —C₀-C₄-alkylene-Q-N(R_(ii),R₁₁), —C₀-C₄-alkylen-N(R₁₂)-Q-N(R₁₃,R_(13′)), —C₀-C₄-alkylen-R₁₄, —C₀-C₄-alkylene-Q-C₁-C₆-alkyl, —C₀-C₄-alkylene-Q-C₃-C₈-cycloalkyl, —C₀-C₄-alkylene-Q-C₃-C₈-heterocyclyl, —C₀-C₄-alkylene-Q-C₅-C₁₀-aryl, —C₀-C₄-alkylene-Q-C₅-C₁₀-heteroaryl, —C₀-C₄-alkylene-O-Q-N(R₁₅,R_(15′)), and —C₀-C₄-alkylene-N(R₁₆)-Q-O—(R₁₇), wherein Q is selected from among —C(O)—, and —SO₂—, wherein R₁₂, R₁₆, are independently selected from among —H, —C₁-C₆-alkyl, and —C₃-C₆-cycloalkyl, wherein R₉, R_(9′), R₁₀, R₁₁, R_(11′), R₁₃, R_(13′), R₁₅, R_(15′), are independently selected from among —H, —C₁-C₆-alkyl, and —C₃-C₆-cycloalkyl, or wherein R₉ and R_(9′), R₁₁ and R_(11′), R₁₃ and R_(13′), R₁₅ and R_(15′) together form a —C₂-C₆-alkylene group, wherein R₁₄ and R₁₇ are independently selected from among —H, —C₁-C₆-alkyl, —C₅-C₁₀-aryl, —C₅-C₁₀-heteroaryl, —C₃-C₈-cycloalkyl, and —C₃-C₈-heterocyclyl, wherein said —C₃-C₈-heterocyclyl optionally comprises nitrogen and/or —SO₂— in the ring, and wherein R₁₄ and R₁₇ are optionally substituted with one or more groups selected from among —OH, —OCH₃, —CF₃, —OCF₃, —CN, -halogen, —C₁-C₄-alkyl, ═O, and —SO₂—C₁-C₄-alkyl, or R₄ and/or R₅ are independently a group of the structure -L₂-R₁₈, wherein L₂ is selected from among —NH— and —N(C₁-C₄-alkyl)-, wherein R₁₈ is selected from among —C₅-C₁₀-aryl, —C₅-C₁₀-heteroaryl, —C₃-C₈-cycloalkyl, and —C₃-C₈-heterocyclyl, wherein R₁₈ is optionally substituted by one or more groups selected from among halogen, —CF₃, —OCF₃, —CN, —OH, —O—C₁-C₄-alkyl, —C₁-C₆-alkyl, —NH—C(O)—C₁-C₆-alkyl, —N(C₁-C₄-alkyl)-C(O)—C₁-C₆-alkyl, —C(O)—C₁-C₆-alkyl, —S(O)₂—C₁-C₆-alkyl, —NH—S(O)₂—C₁-C₆-alkyl, —N(C₁-C₄-alkyl)-S(O)₂—C₁-C₆-alkyl, and —C(O)—O—C₁-C₆-alkyl, and wherein R₄, R₅ and R₁₈ are optionally further substituted by spiro-C₃-C₈-cycloalkyl or spiro-C₃-C₈-heterocyclyl such that together with R₄, R₅ and/or R₁₈ a spirocycle is formed, wherein said spiro-C₃-C₈-heterocyclyl optionally comprises one or more groups selected from among nitrogen, —C(O)—, —SO₂—, and —N(SO₂—C₁-C₄-alkyl)- in the ring, or wherein R₄, R₅ and R₁₈ are optionally further bi-valently substituted by one or more spirocyclic or annellated ring forming groups selected from among —C₁-C₆-alkylene, —C₂-C₆-alkenylene, and —C₄-C₆-alkynylene, in which one ore two carbon centers may optionally be replaced by one or two hetero atoms selected from among N, O and S and which may optionally be substituted by one or more groups on one ring atom or on two neighbouring ring atoms selected from among —OH, —NH₂, —C₁-C₃-alkyl, 0-C₁-C₆-alkyl, —CN, —CF₃, —OCF₃, and halogen; R₆ is selected from among —H, —C₁-C₄-alkyl, —OH, —O—C₁-C₄-alkyl, -halogen, —CN, —CF₃, and —OCF₃; A is —NH—; n is 1, 2 or 3; Z is C or N, characterized in that a compound of formula II

in which R₂, R₃, R₄, R₅, R₆, Z, and n have the meaning as in formula I, is coupled with a primary amine selected from the group consisting of

under conditions facilitating nucleophilic substitution and elimination of HCl.
 2. The process for the production of the compound of formula (I) according to claim 1, wherein R₂ is selected from among —H, -methyl, -ethyl, -propyl, -i-propyl, -cyclopropyl, -butyl, -i-butyl, -t-butyl, —F, —Cl, —Br, —I, —CN, —CH═CH₂, —C≡CH, and —OCH₃; R₃ is selected from among —H, -methyl, and —OCH₃; R₄ is selected from among

R₅ is selected from among —H, and —C(O)—NH₂; R₆ is selected from among —H, —CH₃, —C₂H₅, —O—CH₃, —O—C₂H₅, —F, —CF₃, and —OCF₃; Z is C.
 3. An intermediate compound selected from the group consisting of 